| Abstract|| |
Gastroesophageal reflux (GER) is defined as the movement of gastric contents into the esophagus. This material, which may contain acid, pepsin, bile acids and pancreatic enzymes, has the ability to irritate or injure tissues not adapted to the presence of this potentially noxious material. As reflux may proceed more proximal than the esophagus, other tissues may he affected, both clinical and experimental data have demonstrated that these events nay lead to a variety of esophageal, head, neck and pulmonary complications. Pulmonary manifestations of GER have been the focus of the medical literature, for the last two decades, and in particular the association of GER and asthma has been well recognized. The latter was suggested first by Sir William Osler more than a century ago. Nowadays its presence is well known in terms of gastric asthma, but the importance is till a matter of debate. The prevalence of GER among patients with asthma is generally reported to be higher than in normal but with a wide range from 30% to 90% in several reports. The mechanism by which GER might induce asthma has been a subject of diversity. There are two potential mechanisms whereby GER could produce bronchoconstriction and therefore exacerbate airflow obstruction in asthmatics, the evidences for these mechanisms were reviewed in the text
Keywords: Gastroesophageal reflux, bronchial asthma
|How to cite this article:|
Al Rubaish AM. Gastric asthma: A clinical review. Saudi J Gastroenterol 2002;8:67-73
In 1892, Sir William Osler noticed for the first time that worsening asthma was associated with a distended stomach, but awareness of an association specifically between gastroesophageal reflux disease (GERD) and asthma occurred only during the past two decades , . There is currently considerable interest in this association as evidenced by the publication of many recent related reviews ,
Gastroesophageal reflux (GER) results when Gastric contents are refluxed into the esophagus typically leading to heart burn, regurgitation, dysphagia or odynophagia  . At present the "gold standard" for diagnosing GER is through ambulatory 24-hour esophageal pH monitoring. Pathological GER is present when pH is less than 4.0 for more than 6% of the total recording time. 
The association of GERD with asthma may indicate either that GER causes or triggers asthma or that asthma aggravates GER in a certain proportion of patients. Most studies support the first possibility but the second possibility should not be discounted. With regard to the first possibility, two hypotheses: have proposed a contact of acid with the distal part of the esophagus stimulates acid sensitive receptors and may initiate reflux bronchoconstriction mediated by the vagus nerves , .
Alternatively, microaspiration of gastric contents into the trachea may trigger bronchospasm or sensitize the bronchi to endogenous constrictors such as histamine. It is noteworthy that the esophagus and the bronchial tree share common autonomic innervation because they have common embryonic origins from the foregut  . Factors favoring the second possibility i.e., asthma aggravating GER include air trapping during bronchoconstriction may flatten the diaphragm and lead to reduced competence of LES; during an acute attack of asthma intra-thoracic pressure becomes more negative while intra-abdominal pressure becomes more positive thus increasing the gradient favoring GER; and use of bronchodilators may also induce relaxation of the smooth muscle of the LES. Finally, it is conceivable that both possibilities may operate i.e. GER triggers asthma, which in due course lead to more reflux, thus resulting in a vicious cycle.
The hypothesis that gastric acid in the distal esophagus may reflexly cause bronchoconstriction was investigated by several researchers and this response was abolished by vagotomy  The changes in bronchial tone were demonstrated by changes in FEV, or respiratory impedance. The hypothesis that microaspiration of gastric acid into the bronchial tree may trigger bronchospasm is supported by the findings that as the esophageal pH dropped to less than 4, the tracheal pH decreased to 5.5. However, these findings were not consistent. Gastal et al using two pH electrodes introduced into the esophagus one electrode placed distally and the other one proximally, it was found that distal acid exposure was significantly longer than proximal, this weakened the hypothesis of microaspiration but did not rule it out . The importance of the association of GERD with asthma is indicated by the fact that treatment of GER reduces asthma symptoms, lessens the dose of asthma medication or in a few patients leads to full recovery ,,,,,, . Such beneficial effects of treatment of GER on the course of the disease argue strongly in favour of the possibility that GER triggers or causes asthma.
| Prevalence of the association between GER and asthma|| |
The prevalence of GER among patients with asthma is generally reported to be higher than in normal but with a wide range from 30% to 90% in several reports, while in general population 7-21% were estimated to suffer from GERD symptoms  The wide range in prevalence of GER among asthma patients could be explained by the variation in the methods used for estimating the prevalence, or patient selection. Field and coworkers used a questionnaire based on symptoms of GER  . They found that 77% of asthma patients experienced heartburn, 55% complained of regurgitation and 24% experienced swallowing difficulty. In the week prior to completing the questionnaire, 41% of the asthma patients reported reflux associated respiratory symptoms, and 28% used their inhalers while experiencing GER symptoms.
Sontag et al examined 186 consecutive adult asthmatics employing endoscopy and esophageal biopsy, and found that 79 (43%) had esophagitis or Barrett's esophagus and 58% had hiatal hernia , Kjellen et al examined the prevalence of esophageal dysfunction in patients with asthma and found that 37 of 97 patients with asthma (38%) had evidence of esophageal dysmotility, 26 (27%) had lower esophageal sphincter hypotension and 23 (24%) had a positive Bernstein test  . Many investigators have used ambulatory 24-hour pH monitoring in order to diagnose GER in asthma patients. Sontag et al, examined 104 consecutive asthmatics and 44 controls employing esophageal manometry and 24hour esophageal pH test. Abnormal acid reflex was noted in 82% of asthmatics. Using distal and proximal pH sensors, Gastal et al found abnormal distal GER in 44% of 27 asthmatics ,,, . Other investigators studied selected groups of asthmatic patients. Harding et al evaluated 26 asthmatic patients without reflux symptoms using esophageal manometry and 24-hour esophageal pH monitoring, 62% showed abnormal acid exposure  Irwin et al examined 42 consecutive difficult to control asthma patients and found that 24% of them had clinically silent GER 
| Pathophysiology|| |
The mechanism by which GER might induce asthma has been a subject of debate. There are two potential mechanisms whereby esophageal acid could produce bronchoconstriction and therefore exacerbate airflow obstruction in asthmatics  .
| Microaspiration after reflux (Reflux theory)|| |
Several anecdotal reports described a bronchospastic response to aspirated gastric fluid. In an anaesthetized cat model, intratracheal acidification with 0.2 ml hydrochloric acid resulted in 4.6 fold increase in mean inspiratory and expiratory times and increased total lung resistance  . The vagus nerve was involved in mediating these effects since they were abolished when the animals underwent prior bilateral cervical vagotomy. Intraesophageal acid instillation alone had little effect on pulmonary mechanics. Donnelly et al elegantly demonstrated a relationship between GER and aspiration in three patients with severe asthma by simultaneous recording of intraesophageal and intratracheal pH . A decrease in tracheal pH to less than 5.0 coincided with a decrease in esophageal pH to less than 4.0. The test was then repeated after an antireflux surgery and showed that significant improvement in patients' symptoms and tracheal pH. Microaspiration theory was also confirmed by Jack et al, who monitored simultaneous tracheal and esophageal pH in four patients with severe asthma in an intensive care setting  . Thirty-seven episodes of esophageal reflux lasting more than five minutes were observed and five of these episodes were associated with simultaneous decrease in intratracheal pH. Peak expiratory flow rates decreased by 84L/min when esophageal acid and tracheal acid were simultaneously present versus 8L/min when esophageal acid alone was present. A scintigraphic detection method with simultaneous pH metry in the trachea and dual pH metry in the esophagus was used in a group of 55 patients with GERD and chronic respiratory disorders; microaspiration was detected scintigraphically in 20% of the patients. No aspiration was detected with this technique in the control group  .
| Vagally mediated reflex bronchoconstriction (Reflex theory)|| |
Acid in the esophagus stimulates acid sensitive receptors, initiating a vagally mediated reflex through shared esophageal and bronchial autonomic innervation. The shared autonomic innervation is a consequence of the common origin of the esophagus and bronchial tree from the fore gut 
Mansfield et al demonstrated in a dog preparation an increase in respiratory resistance following esophageal acid installation, a response that was ablated by vagotomy  . A double-blind esophageal acid infusion study was performed by the previous authors on four subject groups: normal controls. patients with asthma and GERD, patients with asthma but without GERD, and patients with GERD only. The patients with asthma and a positive Bernstein test had a 10% increase in total respiratory resistance, the changes in resistance were even more pronounced (72% over baseline) in patients with asthma and GERD and in whom asthmatic attacks were associated with reflux symptoms. Davis and associates further confirmed a role for GER in causing bronchospasm by infusing acid in the distal esophagus of asthmatic children during sleep  . Bronchoconstriction developed in all four children with a positive response to the esophageal acid infusion (Bernestein) test, but in none of the five children with a negative response. All of the respiratory abnormalities occurred during the infusions performed at 4-5 AM but not during the midnight infusion. The authors suggested that a GER-induced exacerbation of asthma required three factors: reflux of gastric acid into the esophagus, an acid sensitive esophagus as revealed by a positive Bernstein test. and a low threshold to broncho constrictive stimuli at the early morning hours.
Likewise, Wright et at studied 136 subjects, measuring airflow and arterial oxygen saturation both before and after esophageal acid infusions and found significant reduction in airflow and arterial oxygen saturation  Pretreatment with atropine abolished these findings, providing evidence for an acid-induced vagally mediated esophagobronchial reflex. In a similar study in Japan, acid was perfused into the distal esophagus of seven asthmatic patients, and measures were taken to ensure that there were no pH changes in the upper esophagus. There was a significant increase in airway hyperresponsiveness with no significant changes in vital capacity, FEVI, peak expiratory flow or respiratory resistance  .
Schan et al performed a series of studies using dual esophageal pH testing to control for possible microaspiration as a confounding factor in these studies  Peak expiratory flow (PEF) rates decreased with distal esophageal acid infusion in normal control subjects, patient with asthma and GERD, patient with asthma but without GERD and subjects with GERD alone. Esophageal acid clearance generally improved PEF except for the patient with asthma and GERD in whom PEF deteriorated further. These effects were not dependent on a positive Bernstein test or on the occurrence of proximal esophageal acid exposure, which is a prerequisite for microaspiration. The patients with asthma and GERD also had an increase in specific airway resistance with distal esophageal acid infusion, which continued to increase despite acid clearance. This suggested that in these patients esophageal acidification led to a prolonged bronchial hyperresponsiveness probably resulting from persistently increased vagal tone or associated release of inflammatory mediators. Subsequent studies by Lodi et al also found that patients with asthma and GERD had exaggerated vagal responsiveness, as compared with age-matched controls, and intravenous atropine partially ablated the broncho constrictive response to esophageal acid, thus indicating the importance of a vagally mediated reflex  .
Bronchial hyperresponsiveness in patients with asthma and GERD was further demonstrated in two studies. In one study the provocation dose of methacholine chloride that produced a 20% reduction in FEV 1 was significantly smaller following intraesophageal acid instillation indicating increased sensitivity  .
Field analyzed 18 studies involving 312 asthmatic subjects, who had undergone esophageal acid infusion or had documented bouts of gastroesophageal reflux  Changes in FEVI, PEF rate and airway resistance occurred in 3%, 35% and 42% of the patients respectively. These changes were generally quantitatively were mild and were partially blocked by inhibitors of substance P, atropine and vagotomy, which suggests that this reflex involves both vagal fibres and neurogenic inflammation. Further evidence that esophageal acid activated a local axonal reflex involving the release of substance P, leading to plasma extravasation in the airways, was found by Hamamoto et al in a guinea pig animal model. The response occurred with the esophagus ligated to prevent aspiration into the airways, and was blocked in a dose-dependent manner by a substance P antagonist. Thus, esophageal acid may stimulate the release of tachykinins, such as substance P, from sensory, neurons, which mediate airway inflammation through a local axonal reflex.
However, conflicting results have also been reported. Wesseling et al found no statistically significant changes in FEVI or respiratory impedance after intraesophageal acidification in 12 asthmatics subjects with GER, suggesting no direct effect of intraesophageal acidification on bronchomotor tone in asthmatics with GER  . Tan et al reported similar findings. They studied 15 patients with nocturnal asthma: no significant changes noted in airflow resistance when acid was present in the esophagus 
| Asthma as a possible cause of GER|| |
Two mechanisms have been suggested to explain how asthma may exacerbate GERD. These include mechanical causes and asthma medication, however few data support these mechanisms.
1. Mechanical causes
It has been proposed that airflow obstruction may increase the negative pleural pressure, and as a result increase the transdiaphragmatic pressure gradient that may reflux gastric contents into the esophagus. However, normal subjects can stand changes in transdiaphragmatic pressure of 300 cm H2O without evidence of GER. Similarly, air trapping and hyperinflation can lead to flattening of the diaphragm and possibly weakening the antireflux barrier. It places the diaphragmatic crura, which normally supplement the lower esophageal sphincter, at a functional disadvantage because of the geometric flattening. Lastly, hyperinflation leads to shortening of the lower esophageal sphincter particularly the intra-abdominal segment, which plays an important role in the antireflux effectiveness of the LES  . No studies to date have proved these theories. In a group of asthmatic. bronchoconstriction produced by inhaled histamine failed to cause reflux.
Michoud et al attempted to recreate mechanical conditions existing inside the thorax during asthma attack by asking the subjects to breath through an added inspiratory resistance designed to decrease inspiratory pressure to -30cm H2O  This maneuver did not produce or increase gastroesophageal reflux in any of the patient.
2. Asthma medications
Theophylline and systemic B2 adrenergic receptor agonist can relax smooth muscle and therefore may reduce LES pressure and trigger or worsen GER in asthmatic patients. Theophylline may both increase gastric acid secretion and decrease LES pressure. While Huber et al failed to demonstrate an increase in GER assessed by pH monitoring when anhydrous theophylline was administered  . Ekstrom and Tibbling reported a 24% increase in the extent of GER, a 170% increase in the frequency of reported heartburn and regurgitation after theophylline administration . Many patients experience a worsening of reflux symptoms while taking theophylline but this was not the case in all studies.
The systemic administration of a B,-adrenergic receptor agonist, but not its inhaler forms, was blamed by some investigators for decreasing LES pressure but this result was refuted by Michoud et al. who tested the effect of oral salbutamol on 10 healthy volunteers and B asthmatic patients against placebo: they found no immediate effect of salbutamol on gastroesophageal motility, peak peristaltic pressure, resting LES pressure or the pressure gradient across LES.
Sontag et al investigated a group of asthmatics taking asthma medications and another group not using such medications, and found no differences between the two groups regarding LES pressure, acid contact time and frequency of reflux episodes  . Thus with the exception of theophylline, the bulk of evidence seems to indicate that asthma medication do not trigger or aggravate GER in patient with asthma.
| The effect of treating GER on the course of asthma|| |
The impact of GER on the pathophysiology of asthma can be evaluated by assessing the effect of treatment of GER on the amelioration or even disappearance of asthma symptoms. Many studies have assessed the effect of medical or surgical treatment of GER on the course of asthma.
| Medical treatment|| |
Antacids, H2-blockers, prokinetic drugs and proton pump inhibitors have all been used by many investigators to treat GER in asthma patients. Not all the studies in the literature showed improvement in asthma symptoms, pulmonary function tests or lowering asthma medication. Some reported studies had design limitations, including minimal attempt to optimize asthma therapy, absence of a control group. small or selected patient populations. inconsistent outcome parameters and lack of objective evidence of acid suppression. More importantly many therapeutic trials were too short to assess the asthma outcome  .
Negel et al. Ekstrom et al and Lorrain et al used cimetidine or ranitidine up to eight weeks and produced results ranging from no benefit to modest improvement of asthma symptoms and pulmonary function tests, , . Larrain et al treated 27 adult asthmatics with non-allergic asthma with 300 mg Cimetidine twice daily for six months  Improvement in pulmonary symptoms and reduction in asthma medication were achieved. Prokinetic drugs were used by others and appears to be effective in children with GERD induced asthma  .
Studies using proton pump inhibitors to control acid reflex have shown the greatest changes in asthma symptoms and pulmonary function tests. In a recent study, Harding et al performed a prospective, pre and post-treatment evaluation of 30 patients with asthma and GERD , . A 30-months course of acid suppressive therapy (20-60 mg/day) of Omeprazole was titrated to control acid reflux by serial 24-hour pH monitoring. Seventy-three percent of patients with asthma and GERD had a 20% increase in PEF and/or a decrease in asthma symptoms by 20%. The asthma responders had improvement in other pulmonary function tests, including FEV1 and mid-expiratory flow rates. and asthma symptoms improved with time. After one month of acid suppressive therapy, there was a 30% reduction in asthma symptoms, at two months a 43% reduction and by three months there was 57% reduction in asthma symptoms. When compared with baseline patients with frequent regurgitation or excessive proximal esophageal acid reflux as revealed by 24-hour pH testing were likely to benefit from this regimen; these factors had 100% sensitivity and 79% specificity in predicting the patients whose asthma would improve with aggressive acid suppression. Levin et al showed also improvement in asthma symptoms following treatment with omeprazole  .
| Surgical treatment|| |
Many studies examined asthma outcome in patients with asthma and GERD, after antireflux surgery, including Nissen's fundoplication, Belsey fundoplication, and troupet repair. Most studies have design flaws, including lack of control group, poor documentation of air flow obstruction (both pre and post operative), poor documentation of asthma severity and definite proof that reflux was adequately controlled in post operative state. Despite these limitations, reviewing the results of 10 trials showed that there was a total of 3 18 patients with asthma improved of this latter group. Over half were cured of their asthma, i.e., they did not require any further asthmatic medications; many were previously on steroids ,
These positive results of improvement in asthma symptoms after long term acid suppression or surgical correction of GER, argue in favour of a significant connection between asthma and GER and should make investigation and treatment of GERD in certain asthmatics advisable.
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Abdullah Mohammed Al Rubaish
Department of Internal Medicine, King Fahad Hospital of the University. P. 0. Box 40085. AI Khobar 31952
Source of Support: None, Conflict of Interest: None