Gastroesophageal reflux and asthma

INTRODUCTION — Gastroesophageal (GE) reflux is common in patients with asthma and has been identified as a potential trigger for asthma [1-4]. GE reflux is a comorbidity associated with severe or difficult-to-treat asthma. An evidence-based guide for the diagnosis, evaluation, and treatment of asthma advises that GE reflux be evaluated and treated, especially in poorly controlled or severe asthma [5]. GE reflux is thought to affect asthma through the activation of vagal reflexes and/or microaspiration.

The term gastroesophageal reflux disease (GERD) refers to symptoms or signs suggestive of reflux [6]. The typical symptoms of GERD are heartburn and regurgitation. Other symptoms suggestive of GERD include dysphagia, chest pain, hypersalivation, globus sensation, odynophagia, and nausea. Esophageal inflammation is not necessarily present.

The relationship between GE reflux and asthma will be reviewed here. Other issues related to GERD are discussed separately. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults" and "Medical management of gastroesophageal reflux disease in adults".)

PREVALENCE — Respiratory symptoms, including those associated with asthma (eg, cough, dyspnea, wheeze, and chest tightness), are increased among patients with gastroesophageal (GE) reflux [7]. Reciprocally, GE reflux is common among patients with asthma. However, GE reflux is most likely not a contributor to asthma in patients without esophageal reflux symptoms, based on the results of randomized trials of acid suppression therapy [8,9]. (See 'Management of patients without symptoms of GERD' below.)

Estimates of the prevalence of GE reflux among patients with asthma have varied from 30 to 90 percent [3,10-23]. Part of the variability may be due to differences in the definition of GE reflux, and the extent to which objective measures of reflux were used.

The following examples illustrate the range of findings:

●Among 341 patients with severe asthma enrolled in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR II) study, 46 percent had GE reflux disease [2].

●A systematic review of 28 studies of patients with asthma found GE reflux symptoms in 59 percent, abnormal 24-hour esophageal pH tests in 51 percent, hiatal hernia in 51 percent, and esophagitis in 37 percent [21].

●One series included 199 patients with asthma who were referred for 24-hour esophageal pH testing [17]. Reflux symptoms were present in 164 patients (82 percent), of whom 118 (72 percent) had increased esophageal acid contact times. Among the patients with asthma and GE reflux, 80 percent reported respiratory symptoms that were associated with esophageal acid events. Of the 35 patients with asthma who did not have reflux symptoms, 10 (29 percent) had increased esophageal acid contact times consistent with the diagnosis of GE reflux.

●In another study, 104 consecutive patients with asthma and 44 control patients underwent esophageal manometry and 24-hour esophageal pH tests [13]. When compared with controls, the patients with asthma had decreased lower esophageal sphincter (LES) pressures, more frequent reflux episodes, and higher esophageal acid contact times (figure 1). Acid reflux, as assessed by acid contact time, was noted in 82 percent of the asthma patients.

●In a population based survey in the United States not limited to individuals with asthma, 6 percent of respondents reported that they had significant (ie, occurring at least twice weekly) heartburn or regurgitation within the last month while 3 percent reported regurgitation. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Epidemiology'.)

●An asthma phenotype evaluation in 1400 Turkish adult asthmatics noted that GE reflux was more frequent in non-allergic and uncontrolled asthma, than among those with allergic asthma [24]. However, GE reflux was not defined carefully in this cohort study.

●GE reflux (physician diagnosed) predicted poor quality of life (Mini-Asthma Quality of Life Questionnaire) in 165 older asthmatics (>65 years old) [25].

●GE reflux was an independent predictor associated with a risk of future asthma attacks in a longitudinal (>3 years) medical record review of 118,981 patients with actively treated asthma from a United Kingdom electronic medical record database [26].

●GE reflux was a frequent comorbidity (46 percent) in patients with severe or difficult-to-treat asthma in 341 patients enrolled in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) II study [2].

PATHOGENESIS — There are three postulated mechanisms whereby esophageal acid may produce bronchoconstriction and therefore exacerbate airflow obstruction in asthmatics: increased vagal tone, heightened bronchial reactivity, and microaspiration of gastric contents into the upper airway (figure 2). Furthermore, gastroesophageal (GE) reflux can illicit neuroinflammation and increase exhaled oxidative stress biomarkers (8-isoprostane) [27].

Increased vagal tone — A number of observations suggest that exposure of the esophagus to acid can cause bronchoconstriction via a vagal mechanism [28-32]:

●A Bernstein test, which is rarely obtained in clinical practice, is performed by alternately infusing saline or acid into the mid-esophagus via a nasogastric tube or manometric assembly. A positive test is defined as reproduction of the patient's symptoms with acid perfusion but not with saline. Among patients with asthma who have a positive Bernstein test, a 10 percent increase in total respiratory resistance is observed [28]. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults".)

●A reduction in peak expiratory flow rate (PEF) was detected during acid infusion into the esophagus in normal controls, patients with asthma plus GE reflux, patients with asthma without GE reflux, and patients with GE reflux alone [29]. Measures taken to improve esophageal acid clearance resulted in improved PEF in all groups except for the patients with asthma and GE reflux. These effects occurred with acid infusion into the mid-esophagus and were independent of proximal esophageal acid exposure (which is a prerequisite for microaspiration) (figure 3).

●Patients with asthma who received an infusion of acid into the esophagus had a reduction in the methacholine dose required to decrease the forced expiratory volume at one second (FEV₁) by 20 percent (PD20), compared with patients with asthma who received an infusion of saline (figure 4) [31]. The effect was abolished with atropine. Thus, heightened bronchial reactivity may result from reflux, presumably mediated by vagal mechanisms [20].

A systematic review summarized the findings of 18 studies that evaluated pulmonary function during esophageal acid perfusion in adults with asthma [33]. FEV₁, mid-expiratory flow rate, and peak expiratory flow rate did not change significantly in 97, 94, and 65 percent of patients, respectively. Changes in airway resistance were noted in 42 percent of patients. It is difficult to reach definitive conclusions based on this review because the studies included different subsets of patients, used different techniques in acid-perfusion, and monitored different airway responses.

The occurrence of respiratory symptoms following esophageal acid exposure may be due to factors other than bronchoconstriction. As an example, esophageal acid perfusion is associated with increases in respiratory rate and minute ventilation, particularly in patients with a positive Bernstein test [34]. This suggests that an increased minute ventilation may be responsible for worsening respiratory symptoms without a decrease in pulmonary function. However, the study was performed in subjects without asthma; whether these data can be applied to patients with asthma remains to be determined.

Heightened bronchial reactivity — Esophageal reflux may also cause neural enhancement of bronchial reactivity, as suggested by the following studies.

●In a study of 105 consecutive patients with asthma, the degree of methacholine reactivity correlated with the number of episodes of reflux during 24-hour esophageal pH monitoring [16].

●In non-asthmatic patients with GE reflux symptoms, 40 percent of patients with esophagitis had positive methacholine bronchoprovocation tests compared with 7 percent of those without esophagitis. Six months of acid suppression therapy (pantoprazole 40 mg daily) reduced positive methacholine test frequency to 13 percent of esophagitis patients showing that airway hyper-reactivity frequency can be reduced in non-asthmatics with esophagitis with GE reflux therapy [35].

●In 92 asthmatics, peripheral airway and total airway resistance were significantly higher in asthmatics with GE reflux symptoms than in asthmatics without GE reflux symptoms [36].

Microaspiration — Microaspiration refers to the inhalation into the lungs of tiny amounts of refluxate from the stomach. This fluid can have a low pH from acidic gastric secretions or a weakly acidic or alkaline pH when the refluxate comes from achlorhydric conditions (eg, atrophic gastritis, use of acid suppressive medication) or from the small bowel.

Esophageal acid causes bronchoconstriction by a vagally mediated reflex. This response is further augmented if microaspiration is present (figure 2). Much of the evidence supporting a role for microaspiration of acid in reflux-induced bronchoconstriction comes from animal studies that found an increase in airway resistance after inhalational or intratracheal exposure to acid [37-39].

There is conflicting evidence from human studies [40]. Among 78 patients with asthma, no correlation was found between bronchoalveolar lavage pepsin levels and asthma severity. Further, no association was noted between BAL pepsin and asthma control, lung function, BAL eosinophil or neutrophil counts, or barium swallow evidence of reflux [40]. In four patients with coexisting asthma and GE reflux, pH probes were placed into the trachea and esophagus [41]. Thirty-seven episodes of esophageal reflux lasting more than five minutes caused a mean decrease in PEF of 8 L/min. During five of these episodes, there was also a fall in tracheal pH, associated with a decrease in PEF of 84 L/min.

Gastric contents that are active in a nonacidic environment can also damage the upper airway epithelium. As an example, pepsin present in gastric juice, is active even in nonacidic pH and is endocytosed by epithelial cells in the upper airways, causing tissue damage [42]. A specific proteomic signature of GE reflux has been noted in induced sputum of patients with severe asthma (compared with less severe asthma and controls) suggesting the presence of a distinct airways phenotype [43]. This phenotype is characterized by elevated amounts of antimicrobial proteins and reduced amounts of proteins that are linked to epithelial integrity. Further evaluation noted three clusters of epithelial gene expression in patients with severe asthma and obesity, GE reflux and proton pump inhibitor treatment [44]. Further research is needed before changing current management strategies.

CLINICAL FEATURES — Characteristics that may predict asthma improvement with GE reflux therapy include symptoms of regurgitation [45], nocturnal asthma symptoms [8], and concurrent symptoms of GE reflux and asthma [8,9,46,47]. As a result, patients with asthma should be questioned about esophageal and extraesophageal manifestations of GE reflux (table 1).

Careful questioning is needed since patients with asthma may not spontaneously identify their symptoms as being related to GERD [46,48,49]. Alternatively, some symptoms that are attributed to asthma may actually be due to GERD. For example, chest tightness may be misinterpreted as asthma, when it is actually due to GERD and cough may be caused by GERD in the absence of asthma.

Pertinent historical findings include:

●Asthma symptoms (cough, dyspnea, and/or wheezing) may be associated with a GE reflux episode, or the patient may use an inhaler while experiencing GE reflux symptoms [14].

●Asthma symptoms are noticed after eating a high fat meal or foods that lower the lower esophageal sphincter (LES) pressure, such as chocolate, peppermint, caffeine, or alcohol [3].

●The patient is taking asthma medication that may promote GE reflux by decreasing LES pressure (eg, theophylline and systemic or inhaled beta agonists) or possibly by increasing esophageal acid contact time (eg, oral prednisone) [3,50,51].

DIAGNOSIS OF GERD IN PATIENTS WITH ASTHMA — The diagnosis of GERD in patients with asthma is often a clinical diagnosis, based on the presence of classic symptoms of GE reflux (eg, heartburn and/or regurgitation). There is no esophageal or respiratory diagnostic test that identifies GE reflux treatment-responsive asthma. For patients with symptoms that are suspicious for GERD but atypical, the next step would be to refer to a gastroenterologist for clinical evaluation and further diagnostic workup [52]. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Diagnosis'.)

MANAGEMENT OF PATIENTS WITHOUT SYMPTOMS OF GERD — Clinically silent GE reflux has been identified in 24 to 62 percent of patients with asthma and early studies suggested that treatment of GE reflux improved asthma control in patients with severe or difficult to control asthma [46,53,54]. However, three clinical trials demonstrated that treatment with proton pump inhibitors did not improve asthma outcomes in the absence of GE reflux symptoms [8,9,55]. Thus, empiric proton pump inhibitor therapy is not indicated in patients with asthma and no symptoms suggestive of GE reflux.

The clinical trials reported the following findings:

●In a study that randomly assigned 412 patients with poorly controlled asthma and minimal to no symptoms of reflux, no difference was found in the number of episodes of poor asthma control between the group taking esomeprazole 40 mg twice daily and that taking placebo for 24 weeks [9]. The outcomes were not affected by the presence or absence of GE reflux determined by pH probe monitoring.

●In the Study of Acid Reflux in Children With Asthma, 306 children with poorly controlled asthma, but without GE reflux symptoms, were randomly assigned to lansoprazole (15 mg/day if weighing less than 30 kg or 30 mg/day if weighing 30 kg or more) or placebo for 24 weeks [55]. No differences in the asthma control questionnaire (ACQ) scores or lung function were noted. Among 115 children with pH probe monitoring results, 49 (43 percent) had evidence of reflux; no difference in asthma outcomes was noted in this subgroup, although the number of patients was small.

●In a separate study, among 201 patients with moderate to severe asthma but no symptoms of reflux, no improvement was seen in peak expiratory flow rate measurements during 16 weeks of treatment with esomeprazole 40 mg twice daily compared with placebo [8].

EMPIRIC THERAPY IN PATIENTS WITH SYMPTOMATIC GERD

Our approach — For patients with moderate to severe asthma and symptoms of GE reflux, particularly those with regurgitation symptoms or nocturnal asthma, we suggest empiric therapy with a proton pump inhibitor (PPI) taken twice daily, 30 minutes before breakfast and dinner for two to three months. PPIs are preferred because they inhibit gastric acid secretion more effectively than H2 blockers [56]. Twice daily therapy is preferred because that was the regimen used in clinical trials, and once daily PPI therapy did not control esophageal acid exposure times in 27 percent of asthmatics with GE reflux [45]. (See "Medical management of gastroesophageal reflux disease in adults".)

The Clinical Practice Updates Committee of the American Gastroenterological Association (AGA) recommends empiric therapy with aggressive acid suppression for six to eight weeks in patients with extraesophageal manifestations of GE reflux, including asthma [52].

All patients should be instructed about lifestyle modifications for GE reflux. (See "Medical management of gastroesophageal reflux disease in adults", section on 'Lifestyle and dietary modification'.)

Evidence that GERD treatment improves asthma — A number of controlled and uncontrolled trials have found an association between GE reflux therapy and improved asthma symptoms among patients with symptomatic GERD. However, the impact of GE reflux therapy on objective outcome measures of asthma control has been variable [8,45,46,53,57-68].

For patients with both asthma and symptoms of GE reflux, the best evidence that PPI therapy improves some asthma outcomes derived from three large, randomized controlled trials that evaluated high-dose PPI therapy.

●One trial randomly assigned 207 patients with moderate to severe asthma plus reflux symptoms to receive lansoprazole (30 mg) or placebo twice daily for 24 weeks [47]. The primary outcome, asthma symptoms, and the secondary outcomes, peak expiratory flow (PEF) and forced expiratory volume in one second (FEV₁), did not improve. However, lansoprazole therapy improved Asthma Quality of Life Questionnaire scores and decreased asthma exacerbations.

●A randomized trial that compared esomeprazole 40 mg once or twice daily to placebo followed 961 patients with moderate to severe asthma and symptoms suggestive of GE reflux disease (GERD) for 26 weeks [69]. In the esomeprazole-treated patients, small, but significant improvements were noted in morning PEF rates, the Asthma Quality of Life Questionnaire total score, and the FEV₁.

●Another trial randomly assigned 770 patients with persistent moderate to severe asthma who were being treated with asthma anti-inflammatory medication to receive esomeprazole (40 mg) or placebo twice daily for 16 weeks in addition to current asthma therapy [8]. Among patients with both nocturnal respiratory symptoms and GE reflux, esomeprazole improved PEF in the morning (8.7 L/min) and evening (10.2 L/min). No significant improvement in PEF was detected among patients without both GERD and nocturnal asthma symptoms.

Improvement in asthma and GERD — Asthma improvement during a three-month empiric trial of twice daily PPI therapy in combination with appropriate lifestyle modifications for GERD is considered diagnostic of GE reflux-triggered asthma. A successful trial may be defined as a 20 percent improvement in peak expiratory flow rates, an improvement in asthma symptoms, or a 20 percent decrease in oral glucocorticoid dose [45]. (See "Medical management of gastroesophageal reflux disease in adults", section on 'Lifestyle and dietary modification'.)

If the empiric trial is successful, we usually continue PPI therapy along with lifestyle modifications, although the PPI dose is often decreased to once daily. Twice daily therapy is resumed if the symptoms recur on the lower dose. Careful monitoring of asthma control should accompany decreases in the PPI dose or discontinuation. It is not known whether substituting an H2 blocker for the PPI will provide comparable control of GE reflux-triggered asthma.

GE reflux is a chronic remitting disorder, and most patients require protracted therapy. (See "Approach to refractory gastroesophageal reflux disease in adults", section on 'Residual acid reflux'.)

Improvement in GERD not asthma — If esophageal symptoms improve with therapy but symptoms and objective measures of asthma do not, it is possible that the patient has GE reflux, but it does not trigger asthma. In this situation, GE reflux would be managed according to usual guidelines. (See "Medical management of gastroesophageal reflux disease in adults".)

Asthma refractory to initial GE reflux therapy — If the empiric therapeutic trial is unsuccessful (ie, no significant improvement in asthma symptoms, peak expiratory flow rate, or systemic glucocorticoid requirement), either asthma is not triggered by GE reflux and GE reflux therapy can be discontinued, or GE reflux was not adequately controlled. To distinguish between these possibilities, esophageal testing can be performed.

Esophageal pH testing and combined esophageal impedance-pH testing — We typically obtain esophageal pH testing in patients who have symptoms suggestive of GERD that are refractory to PPI therapy. When interpreting pH probe data, the percentage time with the intraesophageal pH below 4 is the most useful outcome measure in discriminating between physiologic and pathologic esophageal reflux. Esophageal pH testing is accepted as the standard to diagnose GE reflux with a sensitivity of 93 percent and specificity of 95 percent. Esophageal pH testing also allows correlation of asthma symptoms with esophageal acid events. Limitations of this testing include false negatives and inability to determine the degree to which GE reflux affects a patient's asthma over time [6,70,71]. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Ambulatory esophageal pH monitoring'.)

Esophageal multichannel intraluminal impedance testing is helpful, when combined with pH probe testing, for detection of gastroesophageal reflux independent of pH (ie, both acid and non-acid reflux); however, this testing is not available at many centers. (See "Esophageal multichannel intraluminal impedance testing".)

An AGA Clinical Practice Update advises that a lack of response to aggressive acid suppressive therapy combined with normal pH testing while off GE reflux therapy or impedance-pH testing while on GE reflux therapy significantly reduces the likelihood that GE reflux is a contributing etiology in asthma [52].

The AGA guideline for esophageal pH recording, as well as other AGA guidelines, can be accessed through the AGA web site.

GI referral and endoscopy — Referral to a gastroenterologist is indicated if GE reflux is not controlled on twice daily proton pump inhibitor therapy or if the patient has alarming symptoms (eg, dysphagia, odynophagia, acute involuntary weight loss, or anemia) [72].

As a general rule, upper endoscopy is not indicated for the routine evaluation of patients with asthma and typical symptoms suggestive of GE reflux in the absence of alarming (eg, dysphagia, odynophagia, acute involuntary weight loss, or anemia) or refractory symptoms [72]. GI referral is recommended if eosinophilic esophagitis is suspected. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Upper gastrointestinal endoscopy'.)

The indications for upper endoscopy to evaluate for Barrett's esophagus in patients who require long-term proton pump inhibitor (PPI) therapy is discussed separately. (See "Barrett's esophagus: Epidemiology, clinical manifestations, and diagnosis", section on 'Screening patients for Barrett's esophagus'.)

GE reflux surgery — Consensus has not been achieved on the role of surgery (eg, fundoplication) in patients with asthma-associated gastroesophageal (GE) reflux [73]. Surgical fundoplication for refractory GERD can be useful in selected patients; however, patients may still require medical therapy for GERD after fundoplication. (See "Surgical treatment of gastroesophageal reflux in adults".)

The AGA clinical Practice Update on Extraesophageal GERD notes that a cautious approach should be taken before recommending fundoplication. Surgical fundoplication might be beneficial in patients with a known response of asthma symptoms to PPI therapy who are: (1) unwilling to take PPIs chronically and/or (2) have side effects with PPI therapy or (3) have continued troublesome regurgitation despite PPI therapy [52].

Several studies suggest that surgical therapy is associated with improved asthma symptom control; however, there is little compelling evidence that fundoplication improves pulmonary function in patients with airway obstruction, particularly in patients without symptoms of GERD [1,57,74,75]. A systematic review of 24 studies (only two of which were controlled) estimated that antireflux surgery improved asthma symptoms by 79 percent, but had little effect on pulmonary function [57].

In an uncontrolled study performed after the systematic review, 136 patients with severe, steroid-dependant asthma and active GE reflux still occurring by objective testing despite four to eight weeks of aggressive acid suppressive therapy underwent laparoscopic Nissen fundoplication with concomitant hiatal hernia repair (if present) [76]. After an average follow-up of 24 months, asthma and GE-reflux symptom scores were significantly reduced from pre-operative values. Participants with hiatal hernia (59 percent) had significantly better asthma outcomes (symptoms and asthma medication use) compared with those without hiatal hernia. Multicenter, randomized trials are needed before recommending fundoplication (with or without hiatal hernia repair) for steroid-dependant asthma with difficult to control GE reflux.

Other tests — Other diagnostic modalities, such as barium swallow, capsule endoscopy, Helicobacter pylori testing, technetium-99 sulfur colloid scintigraphic monitoring, salivary pepsin, esophageal mucosal impedance, and inspection of sputum for lipid-laden macrophages, are not recommended for evaluation of GERD in patients with asthma because of unacceptably low sensitivities and specificities [20,52,77,78]. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults".)

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●Beyond the Basics topics (see "Patient education: Gastroesophageal reflux disease in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Gastroesophageal (GE) reflux is common among patients with asthma. Reciprocally, respiratory symptoms, including those associated with asthma, are increased among patients with GE reflux. Estimates of the prevalence of GE reflux among patients with asthma have varied from 30 to 90 percent. (See 'Prevalence' above.)

●Three potential mechanisms have been proposed whereby esophageal acid may produce bronchoconstriction and therefore exacerbate airflow obstruction in asthmatics: increased vagal tone, heightened bronchial reactivity, and microaspiration of gastric contents into the upper airway. (See 'Pathogenesis' above.)

●Patients with asthma should be questioned about esophageal and extraesophageal manifestations of GE reflux (table 1). Pertinent historical findings include asthma symptoms during an episode of GE reflux, use of an inhaler while experiencing GE reflux symptoms, or asthma symptoms after eating certain foods (eg, high fat food, chocolate, peppermint, caffeine, alcohol). (See 'Clinical features' above.)

●Characteristics that may predict asthma improvement with GE reflux therapy include symptoms of regurgitation and nocturnal asthma symptoms. (See 'Clinical features' above.)

●For patients with coexisting moderate to severe asthma and GE reflux symptoms, we suggest a trial of robust therapy for GE reflux (Grade 2B). Such therapy consists of a proton pump inhibitor (eg, omeprazole, esomeprazole, lansoprazole, rabeprazole, or pantoprazole) administered twice per day for two to three months (taken 30 minutes before breakfast and dinner) and lifestyle measures, such as weight loss for overweight individuals and elevation of the head of the bed for those with nocturnal symptoms. (See 'Empiric therapy in patients with symptomatic GERD' above and "Medical management of gastroesophageal reflux disease in adults", section on 'Lifestyle and dietary modification' and "Medical management of gastroesophageal reflux disease in adults", section on 'Proton pump inhibitors'.)

●Chronic GE reflux therapy is included in ongoing treatment regimen, if the empiric therapeutic trial is successful. A successful trial is defined as a 20 percent improvement in peak expiratory flow rates, an improvement in asthma symptoms, or a 20 percent decrease in oral glucocorticoid dose. (See 'Improvement in asthma and GERD' above.)

●Alternatively, if the empiric therapeutic trial is unsuccessful, either asthma is not triggered by GE reflux and GE reflux therapy can be discontinued, or GE reflux was not adequately controlled. A 24-hour esophageal pH test, or combined esophageal impedance and pH test, performed with the patient on antireflux therapy, can distinguish between these possibilities. (See 'Asthma refractory to initial GE reflux therapy' above.)

●Proton pump inhibitor therapy is not indicated for patients with asthma and no symptoms suggestive of GE reflux. (See 'Management of patients without symptoms of GERD' above.)

●Referral to a gastroenterologist is prudent if GE reflux symptoms are not controlled on twice daily proton pump inhibitor therapy or if patients report alarming symptoms including dysphagia, odynophagia, hematemesis, melena, persistent vomiting (ie, 7 to 10 days), acute involuntary weight loss, or anemia. (See 'GI referral and endoscopy' above.)

●Consensus has not been achieved on the role of surgery in patients with asthma exacerbated by GE reflux; endoscopic therapies for GE reflux are considered experimental in this population. (See 'GE reflux surgery' above.)