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ADC Online First, published on September 7, 2017 as 10.1136/archdischild-2017-312890 Review
Respiratory manifestations of gastro-oesophageal reflux in children Fernando Maria de Benedictis,1 Andrew Bush2,3 1
Abstract Gastro-oesophageal 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 paediatric practice, but continue to be entities with more questions than answers. The accuracy of diagnostic tests (ie, pH or pHimpedance monitoring, laryngoscopy, endoscopy) for Correspondence to patients with suspected extraoesophageal manifestations Dr Fernando Maria de of GORD is suboptimal and therefore whether there is Benedictis, Salesi Children’s Hospital Foundation 11, via a causal relationship between these conditions remains Corridoni, I-60123 Ancona, Italy; largely undetermined. An empiric trial of proton pump p ediatria@fmdebenedictis.i t inhibitors can help individual children with undiagnosed respiratory symptoms and suspicion of GORD, but Received 8 June 2017 the response to therapy is unpredictable, and in any Revised 1 August 2017 Accepted 7 August 2017 case what may be being observed is spontaneous improvement. Furthermore, the safety of these agents has been called into question. Poor response to antireflux therapy is an important trigger to search for non-gastrooesophageal reflux causes for patients’ symptoms. Evidence for the assessment of children with suspected extraoesophageal manifestations of GORD is scanty and longitudinal studies with long-term follow-up are urgently required.
Salesi Children’s Hospital Foundation, Ancona, Italy 2 Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK 3 National Heart and Lung Institute, Imperial School of Medicine, London, UK
To cite: de Benedictis FM, Bush A. Arch Dis Child Published Online First: [please include Day Month Year]. doi:10.1136/ archdischild-2017-312890
Gastro-oesophageal reflux (GOR), the intermittent ascent of gastric acid and/or non-acid contents into the oesophagus, is a normal physiological process, which is common, and may be harmless or pathological. Gastro-oesophageal 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 extraoesophageal (respiratory, otolaryngological, neurological, haematological—iron deficiency anaemia, not discussed further). However, the lack of objective standards has led to non-evidence-based practice including overmedication. The expense of managing patients with suspected extraoesophageal reflux symptoms has been estimated as over five times that of patients with symptoms typical of GORD.2 Extraoesophageal manifestations of GORD in adults but not children have been recently reviewed.3–6 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’, ‘oesophageal’, ‘extraoesophageal’, ‘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 (OR, 3.2), wheeze (OR, 3.5) and nocturnal cough (OR, 4.3). Persistent wheezing, asthma and airway hyper-responsiveness 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 vs oesophageal pH monitoring), the severity of asthma and the study design (prospective vs retrospective). The potential pathways of the relationships between asthma and GOR are shown in box 115–18 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.
de Benedictis FM, Bush A. Arch Dis Child 2017;0:1–5. doi:10.1136/archdischild-2017-312890
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Review The role of non-acid reflux
Box 1 Pathophysiological mechanisms underlying the relationship between gastro-oesophageal reflux and asthma
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 extraoesophageal 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 extraoesophageal symptoms in patients refractory to medical treatment with laparoscopic fundoplication suggests that reflux may have some role, and a placebo effect of surgery cannot be excluded.33
Mechanisms that can explain the increased prevalence of GOR in asthmatic patients ►► Increased gastro-oesophageal 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-oesophageal junction through the crural diaphragm due to lung hyperinflation ►► Possible relaxation of the lower oesophageal sphincter induced by asthma medication (ie, β2-agonists, aminophylline) Mechanisms that can explain how GOR 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 oesophagus (reflex theory) ►► Airway oedema, 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)
Recommendations
The role of anti-GOR treatment 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 randomised 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, omeprazole did not improve asthma outcomes.26 A large study on school-age children with poorly controlled asthma and asymptomatic GER showed that the addition of lansoprazole to antiasthma 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. 2
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 improve.35 Surgery is currently the antireflux 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
de Benedictis FM, Bush A. Arch Dis Child 2017;0:1–5. doi:10.1136/archdischild-2017-312890
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Review 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 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 has been proposed as alternative mechanism for adults. Indeed, higher cough sensitivity following acid perfusion into the distal oesophagus 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 oesophageal (or pharyngo-oesophageal) 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 min of a reflux event, then the two are considered associated. Borrelli et al45 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 under-reporting 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 intraoesophageal 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 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 GOR 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%–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 oedema, 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, oesophagogastroscopy and pH-MII testing found that the Reflux Finding Score, a validated 8-items visual score for airway inflammation (subglottic oedema, ventricular obliteration, erythema/hyperaemia, vocal fold oedema, diffuse laryngeal oedema, 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 randomised placebo-controlled trial in adults with symptoms and signs associated with LPRD.53 Unfortunately, there 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 children 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.
Conclusion
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 extraoesophageal reflux in these settings is non-evidence-based. Combined pH-MII monitoring should be reserved for patients with suspected extraoesophageal 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
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Review 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.
Unmet 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 standardised. 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 oesophageal sphincter relaxation (ie, gamma-aminobutyric acid agonists such as Baclofen) which is the basic underlying cause of reflux. Newer gamma-aminobutyric acid agonists with fewer adverse effects will be studied. 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. Funding 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. Competing interests None declared. Provenance and peer review Commissioned; externally peer reviewed. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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Respiratory manifestations of gastro-oesophageal reflux in children Fernando Maria de Benedictis and Andrew Bush Arch Dis Child published online September 7, 2017
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