Many findings support a possible association between gastroesophageal reflux disease (GERD) and asthma in children, but there is not enough evidence to support the causality of this association. Longitudinal studies with long-term follow-up are urgently required to cover the many gaps that persist in this area. Treatment of GERD with proton pump inhibitors (PPIs) in children with uncontrolled asthma does not substantively improve asthma outcomes but large, controlled trials in children symptomatic of both asthma and GERD are lacking. Since there are significant safety concerns for long-term PPIs use in children, physicians should carefully balance their therapeutic decisions in individual cases.
Asthma, gastroesophageal reflux, comorbidity, microaspiration, pH measurement, proton pump inhibitors
Fernando Maria de Benedictis, Anna Maria Tocco and Giuliano Lombardi have nothing to disclose in relation to this article. No funding was received in the publication of this article.
Compliance with Ethics:This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
October 17, 2016 Accepted
January 25, 2017
Fernando Maria de Benedictis, Salesi Children’s Hospital Foundation, 11, via Corridoni, I-60123 Ancona, Italy. E: firstname.lastname@example.org
Gastroesophageal reflux (GER), the intermittent ascent of acid contents into the oesophagus, is a normal physiological process. In contrast, gastroesophageal reflux disease (GERD) is present when the reflux of acid contents causes troublesome symptoms and/or complications.1 Asthma and symptomatic GER are both common disorders in childhood and symptoms of GER are frequently reported among children with asthma.2,3 Historically, respiratory manifestations have been recognized as a potential consequence of GERD, and the relationship between asthma and GERD has been largely debated in the literature.
The aim of this article is to critically review the nature and the clinical aspects of this association in childhood and shed light on one of the most controversial fields of respiratory medicine.
Exploring the association between asthma and gastroesophageal reflux disease
Over the last 30 years, several studies have evaluated the prevalence of GERD in children with asthma. Data are controversial, the differences in the reported prevalence being determined mainly by the criteria used for definition of GERD (that is, symptoms versus laboratory investigation), the asthmatic population included (mild versus severe asthma), the design of the study (interventional, cross-over, retrospective) and the presence of a control group. It is, therefore, not surprising that the mean prevalence of GERD in children with asthma varied from 19.6% to 62.9% when GERD was identified by gastrointestinal symptoms or oesophageal pH monitoring, respectively.4 Few studies included a control group, and the prevalence of GERD was 4.8% in healthy children. The pooled odds ratio for the association between GERD and asthma was 5.6 in controlled studies.4
Exploring the relationship between asthma and GERD in children is hampered by many shortcomings. A global, evidence-based consensus on the definition of GERD in the paediatric population suggests that GERD be defined by using a “patient-centred symptom-based” method.5 However, symptom-based criteria for GERD have significant limitations in children, because reporting of symptoms may be unreliable until the age of eight years.5 Furthermore, asthma and GERD may have similar symptoms in childhood, such as nocturnal cough, chest tightness and exercise-induced discomfort, thus making difficult to determine which children actually have GERD.6 Children and adolescents with GERD more commonly manifest cough and other respiratory symptoms than the typical oesophageal complaint of heartburn in adults.7,8 Indeed, in a recent study in children with poorly controlled asthma, no gastrointestinal symptom differentiated those with and without GER identified by oesophageal pH monitoring.9 Taken together, these findings emphasise that the prevalence of GERD in asthmatic children identified in studies that used symptom scores as inclusion criteria and/or endpoints is likely biased by the inability to differentiate symptoms of asthma from those of GER.
The majority of studies that examined GERD in children with asthma reported oesophageal pH measurement. However, these studies often selected a reflux-index threshold that was lower than that required by evidence-based guidelines, which possibly led to an overestimation of the prevalence of reflux in patients with asthma. On the other hand, pH-metry is limited by the inherent inability to detect non-acid reflux.
From a clinical point of view, the temporal interdependence between GERD and asthma is an important proof of concept for a causal relationship. This aspect was investigated in three cross-sectional studies that assessed whether respiratory symptoms (wheezing, cough) followed episodes of GERD.10,11,12 These studies failed to show a consistent relationship between respiratory symptoms and periods of abnormal oesophageal pH or reflux symptoms, thus underlying that the association of GERD and asthma cannot necessarily be causal, but is rather due to chance alone.
The pathophysiological relationship between asthma and GER has gained much attention by pulmonologists, gastroenterologists and physiologists over the years. The available evidence does not yet clearly indicate whether GER precedes and/or triggers asthma, or asthma precedes and/ or triggers GER. It is, however, likely that each one of these conditions may act as aggravating cofactor of the other.
There are several anatomic and physiological reasons that can justify the increased prevalence of GERD in asthmatic patients. Asthma is known to promote GER by different mechanisms including:
• airway obstruction with concomitant increase of negative intrathoracic pressure, that increases the pressure gradient across the lower oesophageal sphincter;
• cough-induced increase in intra-abdominal pressure, that in turn augments the gastroesophageal pressure gradient;
• lung hyperinflation, that may alter the anatomic connection of the gastroesophageal junction through the crural diaphragm; and
• asthma medications (such as beta2-agonists, aminophylline) that may induce relaxation of the lower oesophageal sphincter.13
On the other hand, two major pathophysiological mechanisms, which are not mutually exclusive, have been proposed to explain how GER may exacerbate asthma:
• microaspiration of gastric content can cause tissue injury of the airway and local inflammation (aspiration theory); and/or
• stimulation of pH-sensitive irritant receptors in the distal oesophagus may both elicit bronchospasm and increase airway hyperresponsiveness through cholinergic pathways (reflex theory).
In addition, neuroinflammatory reflexes may be involved through the release of tachykinins and other neurotransmitters in the airway by nociceptive afferent nerves, thus resulting in airway oedema, mucus secretion, vasodilation and bronchial constriction.14
Patients with GER have significantly reduced laryngopharyngeal sensitivity because of repeated exposure of mucosa to small amounts of acid, thus increasing the risk for aspiration. Chronic microaspiration of refluxate into the airway may present with chronic cough, wheeze and recurrent episodes of pneumonia, and may result in progressive lung disease. However, there is no gold standard test for diagnosing chronic lung aspiration, and determining whether aspiration is a significant cause of respiratory disease remains a challenge in paediatric medicine.15
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Asthma, gastroesophageal reflux, comorbidity, microaspiration, pH measurement, proton pump inhibitors