xsRESPIRATORY COMPLICATIONS OF GASTROINTESTINAL DISEASES

GASTROINTESTINAL DISORDERS AND SYSTEMIC DISEASE, PART I1

0889-8553/98 $8.00

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RESPIRATORY COMPLICATIONS OF GASTROINTESTINAL DISEASES Michele A. Young, MD, and James C. Reynolds, MD

The importance of acid reflux in the pathophysiology of disease of the respiratory tract is becoming increasingly well documented.”, 91 For a substantial percentage of patients with respiratory disorders, gastroesophageal reflux (GER) is the sole cause of these symptoms.4s,95 In another, larger subset of patients, GER contributes with other factors to cause respiratory symptoms. Respiratory disorders suspected of being related to GER include asthma, chronic cough, pulmonary fibrosis, pneumonia, and apnea in infants.2,11, 35, 51, 58, 74 Most importantly, it has been shown that medical and surgical treatments are available for the effective management of these symptoms and related patient morbidity.28,46, 58, 95, lo3 Although these respiratory symptoms are important causes of illness and health care use, patients who suffer from these conditions often do not have typical symptoms of esophageal reflux. Equally important, if GER is not suspected as the cause of the pulmonary disorder, medical management may be unsatisfactory and the patient’s disease considered refractory to treatment. Thus, to treat this problem appropriately, one must first recognize the cause. Recognition that esophageal reflux is associated with symptoms other than those referable to the digestive tract is not new. Patients with acid reflux may present with hoarseness, sore throat, cough, bronchitis, asthma, recurrent pneumonia, intermittent choking, chest pain, and ear From Gastrointestinal Motility Laboratory, Division of Gastroenterology and Hepatology, Carl T. Hayden Veterans Administration Medical Center, University of Arizona (MAY), Phoenix, Arizona; and the Department of Medicine, Division of Gastroenterology and Hepatology, Allegheny University of the Health Sciences-Hahnemann University Hospital (JCR), Philadelphia, Pennsylvania

GASTROENTEROLOGY CLINICS OF NORTH AMERICA VOLUME 27 NUMBER 4 * DECEMBER 1998

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pain without the characteristic symptoms of esophagitis.’, 11, 35, 51, 58, 74, lo3, ll1 These extraesophageal manifestations of GER may be the primary presentation in a large subset of patients.48,50, 58.95 Despite the absence of esophageal symptoms, reflux injury in these patients may be considerable. In fact, erosive, ulcerative esophagitis has been reported to occur in up to 40%.” Barrett’s metaplasia, a compensatory change in the esophageal mucosa from squamous to specialized intestinal epithelium, occurs in up to 10% to 15% of patients with atypical presentations of GER.21,92 The term gas froesophageal reflux disease (GERD) has been used to describe the full spectrum of disorders caused by GER. Although the prevalence of this disorder is difficult to establish, a study of normal individuals revealed that 7% of those questioned had typical symptoms of acid reflux, including heartburn on a daily basis, and 36% had the symptom at least once a month.76Furthermore, daily episodes of heartburn have been reported to occur in 25% of pregnant women.76 A randomized study of 2000 subjects demonstrated a prevalence of 58.1% of white patients with symptoms of heartburn, acid regurgitation, or both. The prevalence of weekly or more frequent episodes of heartburn or acid regurgitation was 19.4Y0.~’ The classic symptoms of heartburn, water brash, and regurgitation are well recognized. Advances in diagnostic technology have shown that the frequency of GERD is much greater than can be appreciated by evaluating patients only for these classic symptoms. The availability of prolonged ambulatory esophageal pH recording has revealed that many 55, 58, l I 3 other symptoms can be attributed to acid reflux disease.50, Although the importance of GERD as a cause of symptoms in other organ systems is well established, this association is often not recognized clinically. This article describes the pathogenesis and clinical syndromes affecting the respiratory tract that are commonly encountered in clinical practice. PULMONARY MANIFESTATIONSOF GASTROESOPHAGEAL REFLUX DISEASE

The association of GERD and pulmonary disorders was recognized as early as 1887.73This association has received increased attention in Up to 50% of patients with the literature in the last few pulmonary symptoms have GERD, however, the hypothesis that this represents a direct causal relationship has not been proven.66,70 The most common pulmonary complications of GERD are as follows: Asthma Chronic bronchitis or cough Recurrent pneumonia Pulmonary fibrosis Apnea

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Asthma

Asthma, an inflammatory disease of the airways characterized by increased airway reactivity to air flow obstruction, affects approximately 20 million people in the United States. Multiple triggers can cause an exacerbation of this reactive airway disease. GER has been proposed as a possible mechanism for triggering asthmatic episodes. Between 45% and 80% of adult asthmatics have evidence of GERD,69,81, 91 an incidence z5 The true prevalence of GER-related similar to that found in ~hildren.~, asthma has been difficult to estimate because of the heterogeneity of the populations and the differences in evaluation techniques. GERD-induced bronchospasm appears to be a particularly important causative factor for asthma associated with nocturnal cough and wheezing, associated with intractable symptoms despite aggressive medical management, and in those patients with no family history or biochemical evidence of atopy.7,25.54. 81.84 Early radiographic studies showed that the prevalence of hiatal hernia and GER by upper gastrointestinal barium studies was 64% and 50% in a hospital-based group of adult patients with severe asthma. These findings were significantly different from those observed in agematched hospital control subjects.69A retrospective review of 300 patients referred for hiatal hernia surgery revealed that 43% of them had associated respiratory problems. Further, 74% of these patients reported a noticeable improvement in their respiratory symptoms after surgery.63 An endoscopic investigation reported that 58% of patients with asthma had a hiatal hernia.89The prevalence of GERD in the outpatient asthma population was estimated by a cross-sectional analysis. Among the asthmatics, 77%, 55%, and 24% experienced heartburn, regurgitation, and swallowing difficulties. Further, at least one antireflux medication was being used by 37% of the asthma patients. These patients also reported an increased use of their inhalers while experiencing GER symptoms. Likewise, inhaler use correlated with the severity of heartburn and reg~rgitation.~~ Gastrointestinal Motility GERD is most common when nocturnal symptoms, particularly cough, are present and in patients with more severe a ~ t h m a . At ~~,~~ night, lower esophageal sphincter pressure rises, but there is little esophageal motor activityz0;thus, if an episode of reflux occurs, it is likely to be prolonged. In asthmatic patients, reflux occurs spontaneously, possibly as a result of increases in the thoracoabdominal pressure gradient or delayed gastric emptying. Moreover, airway protective mechanisms, such as cough, may be diminished during sleep and therefore contribute to the increased finding of nocturnal symptoms. Esophageal dysmotility specifically decreased lower esophageal sphincter pressure, and low-amplitude contractions have been demonstrated with an increased frequency in patients with GERD. Likewise,

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abnormalities in esophageal manometry have been reported in patients with pulmonary disease, such as asthma. Esophageal motility testing was performed on 34 patients with asthma, 15 patients with GER, and 10 normal controls. The results of this investigation demonstrated that 23 of 34 asthmatics had esophageal motor disorders, a number compatible with those patients with GERD and not asthma. No patients in the control group showed any evidence of esophageal dysmotility. Both patients with asthma and those with GERD demonstrated significantly lower lower esophageal sphincter pressure, percent esophageal peristalsis, or amplitude of the contractions compared with the normal control^.^ Similarly, low lower esophageal sphincter pressures were found in a large group of asthmatic patients compared with normal controls.92 The relationship between pulmonary symptoms (aspiration, wheezing or asthma, and nocturnal cough) and pH evidence of GER was evaluated in a large series of patients. This investigation revealed that typical reflux symptoms of heartburn, regurgitation, and water brash were not reliable indicators of GER.80Furthermore, half of the patients did not have endoscopic evidence of esophagitis. Clearance of acid from the esophagus in the upright position in these patients was not significantly different from patients with a primary respiratory disorder. Conversely, patients with reflux and asthma showed significantly delayed esophageal acid clearance when supine.s0Respiratory symptoms, however, were preceded by episodes of GER in only a small subset of patients.80,81 Twenty-four-hour pH ambulatory monitoring was performed in a large unselected group of asthmatics and nonasthmatic controls. In this investigation, the patients with asthma experienced a greater number of reflux episodes, and the amount of intraesophageal acid exposure time was greater than in the control patients. As anticipated, asthmatic patients experienced reflux more frequently when asleep than the controls, and it took them longer to clear the refluxed acid.91Among asthmatics, there was no difference in pH parameters between those who required bronchodilators and those who did not. Therefore, although there is little doubt that reflux and asthma frequently coexist in the same patient, the etiologic significance of this relationship remains controversial. Pathophysiology

Several lines of evidence suggest that acid may cause hyperactive airway disease. Although exact mechanisms by which GERD triggers bronchospasm are unclear, several proposed mechanisms are macroaspiration of gastric contents, microaspiration of gastric contents, and vagally mediated reflux bronchoconstriction (Table 1). Aspiration of refluxed gastric contents into the tracheobronchial tree has been offered as an explanation for the association of GERD and br~nchospasm.~~, *14 Inherent in this mechanism is aspiration of gastric contents into the lung, resulting in an exudative mucosal reaction leading to inflammation and narrowing of the bronchial tree. Mendelson71

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Table 1. MECHANISMS RESPONSIBLE FOR GASTROESOPHAGEAL REFLUX-ASTHMA INTERACTIONS Proposed Effects of GER on Asthma Macroaspiration of gastric contents Microaspiration of gastric contents Effect of Asthma on GER Increased transdiaphragmatic pressure gradient Chronic hyperinflation of diaphragmatic cura Use of methylxanthines and sympathomimetics Cough-induced stress reflux GER

=

Gastroesophageal reflux.

first called attention to the acute asthmalike reaction when gastric contents were noted to have been aspirated during the induction of anesthesia. Subsequent animal studies have confirmed that the aspiration of gastric contents can cause severe bronchospasm.26Experimentally induced bronchospasm has been shown to be associated with a chemical pneumonitis caused by infusion of volumes of 2 to 5 mL of 0.1 N hydrochloric acid into the trachea.26Human studies have demonstrated the aspiration of gastric contents by scintigraphy after eating a technetium 99mradiolabeled meal. Lung scans performed in patients with a technetium 99m-radiolabeled meal were found to be positive in 75% of patients with both pulmonary symptoms and GERD.14 The frequency and severity of gastric aspiration may be worsened by the presence of esophageal motility disorders or structural lesions in the esophagus, which impairs the esophageal clearance mechanisms. The clinical outcome of the aspiration depends primarily on the mucociliary function of the tracheobronchial tree and secondarily on the volume and composition of the aspirate. Subsequent studies have not confirmed these original observations.12 Furthermore, because of the absence of aspiration pneumonitis in a large proportion of patients with reflux-associated pulmonary disorders: alternative explanations have been postulated to explain the relationship between GERD and pulmonary symptoms. Microaspiration of minute amounts of gastric contents at a low pH 74 into the tracheobronchial tree may also cause bronchoconstriction.42~ Animal studies have demonstrated that stimulation of tracheal receptors located in the upper airway epithelium is associated with vagally mediated reflex bronchoconstriction.lo2, Tuchman et allo2investigated the latency of the airway responsiveness in cats after an acid infusion into the trachea and esophagus. Tracheal infusions as small as 0.05 mL of 0.2 N hydrochloric acid resulted in an 4.65-fold increase in total lung resistance, whereas much larger infusions of 10 mL of 0.2 N hydrochloric acid into the esophagus produced only a 1.47-fold increase in total lung resistance. Intraesophageal infusion of normal saline did not produce any changes in pulmonary resistance. These results suggest the importance of a reflex pathway in the trachea and esophagus in the pathogene-

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sis of GER and pulmonary disease. A variety of acidic substances has 71, lo2 Tracheal been shown to stimulate reflux bronchial constriction.26* acidification has been shown to produce marked increases in airway resistance, and further, these effects were abolished after a surgically induced bilateral vagotomy.26,lo2 In humans with asthma, simultaneous tracheal and esophageal pH sensors recorded several reflux episodes lasting greater than 5 minutes. More importantly, PEFR measures decreased by 84 L/min when acid was present in both the trachea and the esophagus. In contrast, only an 8 L/min decrease was recorded when only intraesophageal acid was recorded.49These results suggest that minute volumes of hydrochloric acid, with a pH comparable to gastric acid, may stimulate a bronchoconstrictive response in a normal airway. The reflux of gastric contents may induce bronchoconstriction by stimulating esophageal mucosal receptors, which subsequently initiates 66, 67 Intraesophaa vagal nerve mediated reflex bronchial constri~tion.~~, geal hydrochloric acid challenges experimentally infused into dogs caused a significant fall in the ratio of total respiratory resistance to functional residual capacity.66This change was not duplicated in these same dogs after vagal nerve interruption. In human subjects, significant increases in total respiratory resistance and reduced flow rates at 25% of vital capacity were seen shortly after intraesophageal acid infusions but not after infusion of normal saline or infusions of neutralized gastric contents.67Furthermore, symptomatic relief obtained with antacids was paralleled by improvement in pulmonary function. These results suggest that reflux-induced bronchoconstriction can be inhibited by neutralization of esophageal acidity, by anesthesia of esophageal receptors, or by vagal nerve blockade.65Other studies, however, have found no influence of esophageal acid infusion on pulmonary function or clinical pulmonary symptoms.38,97 Esophageal acid infusion in both asthmatics and nonasthmatic patients failed to elicit an obstruction to air flow. In asthmatic patients, however, the intraesophageal hydrochloric acid infusion resulted in a significant decrease in maximal expiratory flows compared with the nonasthmatic patients. In the asthmatic subjects, this decrease in expiratory flow was significantly greater during infusion of hydrochloric acid than during the saline infusion^.'^ Heme et a138evaluated the effects of intraesophageal acid infusions on maximal expiratory flow at 50% of vital capacity in 12 randomly selected asthmatic patients. In all subjects, hydrochloric acid perfusion did not change the midexpiratory flow rates at 50% of vital capacity. These acid infusions did, however, potentiate the bronchoconstriction induced by isocapneic hyperventilation of dry air or with a methacholine challenge. These observations suggest a mechanism of stimulation of esophageal receptors triggering a vagally mediated bronchoconstriction. Diurnal variation in airway resistance, which peaks in the early morning hours, has been found to be exaggerated in asthmatics with primarily nocturnal symptoms.” Nocturnal GER may contribute to this increased airway resistance and worsening symptoms of asthma. In asthmatic children who had reflux and a positive Bernstein test, esopha-

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geal infusion could provoke asthma symptoms between the hours of 4 and 5 A.M., when the airway resistance because of diurnal rhythm is already at its peak. These asthmatic symptoms, however, were not proSpaulding et examined vokable by acid infusions at an earlier a group of asthmatics who also reported symptoms of GER, specifically pyrosis. They found that intraesophageal infusion of hydrochloric acid resulted in impaired air flow in almost 60% of patients with nocturnal asthma and pyrosis. Further, improved pulmonary function tests were noted after administration of antacids. Asthma and Coexisting Chronic Obstructive Pulmonary Disease

Alternatively, bronchospasm and chronic obstructive pulmonary disease (COPD) may trigger GERD. An important mechanism for GERD in such patients is the increase in the transdiaphragmatic pressure gradient (Fig. 1). Normally, pressure in the stomach is positive relative to the pressure in the esophagus. Coughing causes a marked increase in intragastric pressure and frequently leads to stress reflux, even in otherwise healthy individuals. Second, during an episode of bronchospasm, more negative intrapleural pressures are generated during inspiration, which amplifies this pressure difference and predisposes to reflux. Third, the effects of chronic hyperinflation on the diaphragmatic crura, which is an anatomic and physiologic part of the lower esophageal sphincter mechanism, may have an effect on lowering lower esophageal sphincter pressure.65Hyperinflation also leads to flattening of the diaphragm in patients with obstructive lung disease. This diminishes the angle of His and the ability of the diaphragm to act as an antireflux barrier. In addition, increased air flow resistance in COPD causes an elevated pressure gradient between the negative intrathoracic pressure and positive intra-abdominal pressure, which predisposes to GERD. Consequently the functions of the diaphragm as a reflux barrier may become impaired. Therefore the exact relationship between asthma and GERD has been debated, and causative roles have been difficult to assign. Effects of Asthma Medications on GER An important consideration in asthmatic patients with coexisting GER is the effect of asthma therapy on reflux. Early animal studies showed that isoproterenol and theophylline produced a dose-dependent fall in lower esophageal sphincter pressure.35Several studies have suggested that bronchodilator therapy commonly used by asthmatics decreases lower esophageal sphincter pressure and thus promotes 23 Theophylline, a methylxanthine, is a commonly used drug in GERD.22, the treatment of asthma that has been implicated in the production and potentiation of GER in subjects with asthma.', Manometric studies have shown that lower esophageal sphincter pressure is decreased in normal and asthmatic patients with theophylline treatment.96Theoretically, this decrease in lower esophageal sphincter pressure could exacerbate GER.

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,UES

Esophageal clearance: Crural

peristalsis, intraluminal secretions

A Forced inspiration more negative intrathoracic pressure Increased transdiaphragmatic pressure gradient

Histal hernia

intra-abdominal

forced inspiration

Figure 1. A, Normal anatomic and physiologic factors that protect against gastroesophageal reflux. B, Anatomic changes associated with COPD, including flattening of the diaphragm, increases in intra-abdominal pressures, and loss of the angle of HIS. UES = upper esophageal sphincter; LES = lower esophageal sphincter.

Aminophylline has been shown to increase acid secretion in patients with COPWO and to decrease lower esophageal sphincter pressure in

opossum^.'^, 33 Ambulatory esophageal pH data implicating theophylline as a cause of reflux is less convincing. Twenty-five adult patients with moderateto-severe asthma and a history of GER underwent two independent 24-hour pH studies. One was obtained while the patient was taking theophylline, and the other was done when theophylline levels were undetectable in the patient’s blood. This study showed that symptoms

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of heartburn and regurgitation increased by more than 170% during the theophylline period. Furthermore, a significant increase in total reflux time occurred both during the day and at night while the subjects were taking theophylline.23Conversely, in a randomized, double-blind trial comparing 1 week of slow-release theophylline and placebo therapies in adult patients with asthma, no differences were found in 24-hour ambulatory pH measurements in the placebo or drug groups.41Similar findings were also reported for normal and asthmatic children when given theophylline.8 The conflicting data and clinical significance of these studies are not entirely clear. It does seem reasonable, however, that in view of its potential to exacerbate GERD, theophylline should be used with caution as maintenance therapy in asthmatic patients with GERD. Its role in those patients without known GERD remains less clear and deserves further study. Lower esophageal sphincter responses to adrenergic agents have been described in both animal and human subject^.'^, 22, 33 a-Adrenergic agonists cause lower esophageal sphincter contraction, whereas P-adrenergic agonists, also frequently used in the treatment of asthma, administered either orally or intravenously can lower lower esophageal sphincter pressure. Carbuterol, a selective P,-adrenergic agonist, significantly decreased mean lower esophageal sphincter pressure in normals and in achalasia patients, who have abnormally high basal lower esophageal sphincter pressure.22Conversely, intraesophageal pH monitoring failed to show differences between normal and asthmatic children when administered metaproterenol sulfate, a P-agonist.8 The clinical consequences of these findings remain unclear because other studies have shown no difference in acid reflux parameters in asthmatic patients receiving p-agonist therapy compared with those not receiving this therapy.91,92 Likewise the use of 24-hour intraesophageal pH monitoring in 10 children and 10 adult controls was studied before and after treatment with placebo, oral theophylline, and oral metaproterenol. The results of the investigation indicated that although episodes of asymptomatic GER did occur, no adverse effect was noted on pulmonary function. Thus, oral bronchodilator therapy may result in episodes of GER; it does not, however, provide evidence that these medications produce adverse respiratory effects.s In a cross-sectional survey of 109 patients with asthma, no patient reported any association of symptomatic GER with the use of their asthma medication^.^^ Sontag et a19' performed 24-hour pH studies on patients with asthma and normal controls. Among the asthmatic patients taking theophylline or P-agonists, there were no differences in the frequency or duration of esophageal reflux recorded by the asthmatics that were not taking these medications. Treatment Outcomes in Asthma and GERD

Surgical Therapy Thus, it is clear that most patients with asthma have reflux, that bronchospasm and COPD can cause GERD, and that acid reflux can

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cause bronchospasm. The importance of GERD as a cause or as an exacerbating factor of asthma remains an incompletely resolved issue. The most convincing support for the causative role of GERD in the development of bronchospasm stems from the improvement of respiratory symptoms after medical or surgical treatment of GERD. Figures 2 and 3 illustrate the effects of trials of medical or surgical antireflux therapies on symptoms of asthma. Control of acid reflux by fundoplication has suggested a more convincing role for GERD as a causative factor in asthma. Early uncontrolled series using surgical fundoplication for the treatment of asthmatic patients with symptoms of GER showed improvement in pulmonary function in 75% to 90% of patients.78,lo3 Nissen fundoplication was performed on 24 patients, with results demonstrating complete resolution of pulmonary symptoms in 6 patients, significant improvement in 16 patients, and no response in only 2 pat i e n t ~Similar .~ results were reported by other surgeon^.'^, 82, 98 Objective measurements of peak expiratory flow and percent variation in peak expiratory flow when evaluated parallel symptomatic improvement.yo Sontag et alYoreported the findings of antireflux surgery performed on 13 adults with asthma and GER. The results of this study revealed that 6 of the 13 patients were completely free from all asthmatic symptoms. Six additional patients had marked improvement in their asthmatic symptoms, and in only one patient did asthma symptoms remain unchanged. Furthermore, in all patients who had a symptomatic improvement, the patients were either able to stop or able to decrease the use of

.

~

(n=15) H2RA

rrin 391 =27) !RA

Meir

1994 (n=27) PPI

Ford 1994 (n=ll) PPI

1

R

199 (n=3 PPI

1

Teichtahl 1996 (n=20) PPI

Figure 2. Effects of medical antireflux therapy on symptoms of asthma. Results of selected studies are shown as a percentage with a good to excellent response to treatment. In all studies, patients were instructed on antireflux precautions. Additional treatments used in each study are shown: ANTA = antacids; H2RA = H, antagonists, cimetidene, or ranitidine; PPI = proton pump inhibitor (e.g., omeprazole).

RESPIRATORY COMPLICATIONS OF GASTROINTESTINALDISEASES

Author

1

L-

Year Number

Overholt 1966 (n=37)

Ursck

1967 (n=27)

-~ Berqr : 1981 (n=21)

Sontag

DeMeester

1987 (n=13)

1989 (n=17)

PemnFayolle 1989 (n=44)

731

lardln

Wain

1989 (n=10)

1991 (n=26)

Figure 3. Effects of antireflux surgery for symptoms of asthma. Results of selected studies are shown as a percentage of patients with a good to excellent response to treatment. A Nissen fundoplication was the most frequently performed surgical procedure. A Belsy Mark V fundoplication was rarely used.

their asthma medications. A larger series of 44 patients surgically treated for asthma with an antireflux procedure reported only 25% of patients became asymptomatic after the procedure. Forty-one percent of the patients, however, reported some degree of improvement in asthmatic symptoms after a Nissen fundoplication.82Tardiff et a198evaluated the Nissen fundoplication in 10 patients with both asthma and GERD. Approximately 50% of the patients had some degree of improvement in the pulmonary symptoms. Although the surgical series demonstrate promising results and help to establish a causal association between asthma and GERD, the interpretation of these trials is limited by the poor study designs, specifically the lack of a control or medically treated group for comparison and the absence of objective measures of pulmonary function either preoperatively or postoperatively. Medical Therapy

Studies that examined objective responses to treatment provide greater insight into the controversy. A double-blind, crossover trial of 20 adults with GERD-related asthma demonstrated marked improvement in pulmonary symptoms and daily peak flow measurements with cimetidine therapy in 18 of the 20 patients studied. Ranitidine therapy given over 8 weeks to 15 patients with asthma and symptomatic GER resulted in amelioration of reflux symptoms, marked improvement in pulmonary symptoms, and a significant improvement in spirometry readings, including mean forced expiratory volume in 1 second (FEV,), forced vital

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capacity (FVC), FEV, /FVC, and slow vital capacity.37Although there was partial improvement in reflux symptoms shortly after the initiation of therapy, improvement of pulmonary symptoms was delayed by approximately 4 weeks. The variability seen in symptomatic responses to behavioral modification and antacids is likely to be the result of poor standardization of this treatment approach and the poor response rate produced by these treatments for both typical and extraesophageal 57 Similar medical therapies gave inconsistent beneficial re~ymptorns.~, sponse rates. The reasons for these discrepancies are likely due to the differences in patient selection, the paucity of controlled trials, the lack of randomization, and the small sample sizes studied. A randomized, controlled trial comparing medical treatment with cimetidine or antireflux surgery to placebo in 90 patients with asthma showed significant clinical improvement in both treatment groups. FEV, and midexpiratory flow rate also improved in both treatment groups but not in the placebo In this series, improvement in pulmonary symptoms was found to be equally efficacious in the medical and surgical treatment groups. Conversely, Sontag et al9I randomized patients with asthma to either placebo, ranitidine 150 mg orally two times a day, or surgical therapy with a Nissen fundoplication. In the surgical group, 75% of the patients had significant improvement or symptom resolution compared with only 9% and 4% in the H,-receptor antagonist and placebo groups. Omeprazole is a proton-pump inhibitor that has consistently shown a greater effect in reduction of gastric acidity, improvement in endoscopic evidence of GERD, and improvement in typical GER symptoms 87, Io5 Surprisingly, only 4 of 15 compared with other medical therapies.M* (27%) patients with asthma and GER demonstrated an improvement in pulmonary symptoms and in FEV, after 6 weeks of omeprazole therapy70 Gastrointestinal symptoms of reflux improved in all patients. These unexpected results may be partially due to the small sample size and the inclusion of smokers in the sample. The beneficial effect was more pronounced in the asthma patients who had the most convincing evidence of GER and in those in whom the dose administered healed esophageal ulcerations. Furthermore, although evidence of pulmonary improvement was evaluated objectively by an increase in FEV,, symptomatic improvement was not consistently addressed. Ford et aP9 failed to find any subjective symptomatic or objective pulmonary function improvement in a small group of adult asthmatics with 4 weeks of omeprazole 20 mg a day. These findings may be explained by the low dose of therapy used in this study. It has been suggested that the beneficial effects of antisecretory therapy on asthmatic symptoms require doses in excess of those normally used to treat typical reflux symptoms. It has also been suggested that a response to treatment for the atypical symptoms, especially asthma, may not be seen for several months after initiation of therapy. Accordingly a study confirmed the control of acid reflux by serial pH testing while titrating the dose of omeprazole from 20 to 60 mg, as required. Patients were maintained on adequate suppres-

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sion for 3 months. Responders were identified by a priori definitions: asthma symptom reduction by greater than 20% or peak expiratory flow increase by 20%. Twenty-two (73%) patients were asthma symptom or peak expiratory flow responders: 20 (67%) symptoms and 6 (20%) peak expiratory flow responders. Responders reduced their asthma symptoms by 57%. Eight patients (27%)required more than 20 mg/d of omeprazole to control GER. Patients who eventually required more than 20 mg/d could not be reliably identified by clinical parameters or their initial pH study.36Teichtahl et a199performed a double-blind, randomized, placebocontrolled, crossover study of 20 adult patients with asthma and 24hour pH evidence of GER. During the treatment phase of this study, patients received omeprazole 40 mg/d for 4 weeks. Although evening peak expiratory flow rates improved significantly, asthma symptoms, inhaled p-agonist use, spirometric measures, and histamine bronchial responsiveness did not change with therapy. The primary differences in these latter two studies are the higher doses of medication and the longer duration of therapy used in the former study. The efficacy, dose, and duration of proton-pump inhibitor therapy for patients with GERrelated asthma remains unclear. Therefore further studies of protonpump inhibitors in asthmatic patients are needed to clarify its role in the treatment of asthma.

Cough Cough is a common clinical problem, being one of the most common complaints for which patients seek medical attention. Chronic cough is a cough that lasts for at least 3 weeks, without any other associated symptoms, including shortness of breath or hemoptysis. In the evaluation of chronic cough, GER has been established as a cause of the cough in 6% to 10% of patients.46In these patients, the diagnosis of GERD was made on the basis of reflux symptoms plus the demonstration of abnormalities on endoscopy or esophageal pH monitoring and disappearance of cough with antireflux therapy. Other studies that used 24hour pH monitoring to define the presence or absence of GER in the evaluation of chronic cough found that almost 40% of patients presenting with cough also had associated GER.Io4 Microaspiration from proximal reflux produces laryngeal inflammation with or without bronchial inflammation, which results in symptoms of hoarseness and cough. Twenty-four-hour ambulatory pH monitoring with distal and proximal pH probes has shown some degree of proximal reflux, including into the hypopharynx in 9 of 15 patients in one In a similar study, only 10.7% of the patients studied demonstrated proximal esophageal Tracheal pH monitoring via a pH probe inserted through the cricothyroid membrane has also been used to attempt to quantify acid aspiration, but results to date have An earlier retrospective review of 20 patients who been inconcl~sive.~~ presented to a tertiary care center with chronic cough found that almost

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75% of those patients complained of symptoms suggestive of GER.28In addition, more than half of these patients had radiographic or endoscopic evidence of GER. Phase 1 and 2 antireflux therapy, including antacids, H,-receptor antagonists, and prokinetic medications, resulted in symptomatic improvement in 14 of the 20 patients.28Irwin et a148 prospectively evaluated nine patients complaining of chronic cough with prolonged esophageal pH monitoring. Although only three patients had symptoms consistent with reflux, all patients had esophageal pH evidence of reflux. During the entire study period, the number of coughs was significantly correlated with the number of total refluxes, the number of reflux episodes lasting 5 minutes or longer, and the percent total time that the pH was less than 4 in the distal esophagus. Further support for the relationship of GER and cough was established by the relief of symptoms in greater than 80% of the patients after therapy with H,receptor antagonists. A 24-hour ambulatory pH study comparing normal controls and patients with chronic cough revealed that the patients experienced significantly more and longer episodes of reflux per 24 hours compared with the controls." Aggressive antireflux therapy, including either omeprazole 20 to 40 mg/d or antireflux surgery, in 25 patients with severe GER and chronic cough was performed to evaluate the relationship between chronic cough and GER.Io9Improvement in the typical symptoms of reflux was noted in 22 of the 25 patients. Further, 20 of the 25 patients showed some degree of improvement in their cough. In children, the prevalence of GER as a cause of chronic persistent cough is 4% to 15%.4O These studies suggest that a chronic persistent cough that remains unexplained after a standard diagnostic assessment is likely to be associated with GER. It has been suggested that cough results from gastric acid stimulating a distal esophageal tracheobronchial reflex mechanism with no evidence of microaspiration or proximal esophageal refl~x.4~ The afferent pathway is inhibited by the esophageal instillation of a local anesthetic, such as lignocaine. The efferent pathway is inhibited by nebulized ipratropium bromide.45This reflex arc may be the mechanism by which reflux disease leads to cough in patients with chronic cough and GER. Intraesophageal acidification, however, may not be the sole mediator of this reflex arc. Pneumonia Recurrent aspiration pneumonia has also been reported as a pulmonary-associated complication of GERD.", 24, Io8 Causative mechanisms most likely include aspiration of gastric contents or aspiration of bacteria from the upper digestive tract. Pulmonary scintigraphy documented recurrent pulmonary aspiration of gastric contents in 50% of patients with pneumonia and GER.', Each of these patients had low lower esophageal sphincter pressures. Children who experience recurrent episodes of pneumonia often have evidence of GER.", 24 The pneumonias

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seen in these children are frequently multilobular, in contrast to patients without evidence of re flu^.^^ An evaluation of 20 patients with recurrent pneumonia using 24-hour ambulatory pH monitoring showed that 18 of 20 patients had abnormal proximal or distal pH reflux A comparative study evaluated esophageal manometry and pH monitoring in infants with GER and no sequela of the disease or GER and recurrent pulmonary disease. The results of this investigation indicated that with respect to esophageal manometry, 24-hour pH monitoring, and gastric emptying, these two groups of infants were significantly different. With respect to esophageal manometry, lower esophageal sphincter pressure did not differ between the groups; the groups did, however, differ in peristaltic function. The infants with pulmonary disease had significantly decreased peristaltic amplitude in the distal body of the esophagus and a significantly increased number of nonperistaltic sequences. Gastric emptying of isotope-labeled cow's milk formula after 1 hour was significantly delayed in the infants with GER and pulmonary disease compared with the infants with GER and no serious sequelae. The pH monitoring studies provided the clearest delineation of the patient groups. Those infants with recurrent pulmonary disease had more severe reflux by pH monitoring with 36.3% of reflux time postprandially compared with 19.0% reflux time postprandially in the group of infants with GER and no evidence of pulmonary disease.39As reported, infants with severe reflux have significantly decreased peristaltic amplitude in the distal esophagus and significantly more abnormal esophageal peristalsis. This sequence suggests an important role for impaired acid clearance from the esophagus in GER of infancy. Chronic lung disease from repeated aspiration of refluxate may develop, with radiographic findings consistent with bronchopulmonary dysplasia. A declining pulmonary status or the presence of gastric contents in tracheal aspirates of infants with bronchopulmonary dysplasia should raise the suspicion of GERD.4 In adults with percutaneous endoscopic placement of feeding gastrostomies, an increased incidence of pneumonia has been reported in those patients with coexisting GER.86Gastric reflux may be an important cause of nosocomial pneumonia in patients who are on ventilatory assistance in an intensive care unit setting.'08 Pulmonary Fibrosis There is compelling evidence that repeated aspirations of small volumes of gastric secretions over time may provoke a progressive fibrotic pulmonary response in some individuals. Hiatal hernias and GER have been demonstrated in the vast majority of patients (85%)with idiopathic pulmonary fibrosis in a study by Mays.69GERD may also contribute to the pulmonary fibrosis associated with progressive systemic sclerosis in some patients.52The vast majority of progressive systemic sclerosis patients have proximal esophageal reflux by ambulatory pH monitoring. More importantly, a direct correlation may exist between

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the degree of GERD and the severity of pulmonary fibrosis as determined by carbon monoxide diffusing capacity. The esophageal motility abnormalities seen in these patients may further worsen esophageal acid clearance and contribute to GER and pulmonary symptoms. In contrast, 39 patients with progressive systemic sclerosis were evaluated for GER and changes in pulmonary function. In this investigation, there were no differences in total lung capacity and FVC relative to the presence of either distal or proximal pH as measured by 24-hour dual pH monitoring.lo1 Apnea

There is growing evidence suggesting that GERD may be a contributing factor to infant apnea.12,94, lo7 GER in the infant differs somewhat from that in the adult in that infantile regurgitation appears to be caused by active expulsion of gastric contents into the esophagus. The primary mechanism of expulsion in regurgitation is a series of sudden contractions of the diaphragm and abdominal respiratory muscles. Sudden elevation of gastric pressure is the force that expels gastric contents from the stomach.100In a group of infants with a history of both frequent regurgitation and clinical apneic spells, the effect of airway protective behavior on respiration was evaluated. It was determined that the normally occurring respiratory pause and airway closure that immediately follows regurgitation can often be prolonged. With the cessation of respiratory air flow, repeated swallowing occurred in some infants, and ineffectual efforts to breathe were common. These respiratory events were identified as obstructed inspiratory efforts and were viewed as a consequence of the reflexive airway closure that accompanies regurgitation. Bradycardia may also be associated with these longer-duration apneic episodes. A strong statistical correlation of increased frequency of both short and prolonged apnea during the 10-second period immediately after regurgitation, as compared with apnea during control, regurgitation-free periods, was found.*OO It was further speculated that when prolonged rather than brief apnea occurs during regurgitation, there is a failure of arytenoidal closure mechanisms that normally function to prevent extensive contact of gastric fluid with receptors in the interarytenoid space.” The consequences of such extensive fluid contact with the interarytenoid space and possibly areas lower down in the larynx would be to prolong the airway protective reflex process during increased neural receptor excitation, thus causing sleep apnea of increased duration. Awake apnea generally occurs within 1 hour of feeding and is described as a sudden startled or a staring expression and rigid posturing with subsequent hypotonia. Fifteen infants with these symptoms were compared with a control group of infants using impedance pneumography, nasal air flow, and 24-hour intraesophageal pH m ~ n i t o r i n g . ~ ~ Of the infants with awake apnea, 100%had marked GER by pH monitor-

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ing, and 87% showed documented airway obstruction occurring with the reflux. In contrast, none of the infants in the control group had such episodes. Barium esophagrams of 160 infants examined for apneic episodes showed GER to be the most common abnormality, occurring 54% of the time.35Seventeen infants with near-miss sudden infant death syndrome were found to have frequent reflux episodes and pulmonary The temporal relationship between apneic episodes and GER demonstrated that apnea was equally likely to occur during the control non-GER segments as during the GER episodes when examined by esophageal pH monitoring.'07 Thus, although an association between GER and apnea has been demonstrated in the literature, a temporal relationship has not yet been identified. The hospital records of 39 infants who underwent Nissen fundoplication for documented GER who presented with acute respiratory symptoms were retrospectively reviewed and showed substantial improvement in respiratory symptoms in 94% of the infants after the DIAGNOSIS

The diagnosis of atypical GERD primarily depends on a strong clinical suspicion. A careful history may elicit symptoms suggestive of GERD, such as heartburn, regurgitation, or frank aspiration. Because up to one third of patients with pulmonary symptoms of GERD have no esophageal symptoms, a high index of suspicion is needed to identify GERD as a contributing factor.2,58, 62, 95 The suspicion for GERD-induced symptoms should increase if symptoms worsen after large meals or when supine. Other historical factors that should raise a suspicion for the diagnosis of atypical GERD include resistance to conventional therapy and a predominance of nocturnal symptoms. A variety of diagnostic tests are helpful in defining the presence of GERD. Barium esophagrams provide little important information regarding the presence, extent, and volume of reflux material. Barium studies in asthmatic children have shown a variability in the incidence 25, 35 In of GER from 11% to 100% of subjects with a mean of 69Y0.~. adults, however, the yield of barium studies has been less than 50%.'0*77 Furthermore, barium studies correlate poorly with more sophisticated measures of GERD. Radiography Radionuclide scanning is a specific test in demonstrating GER or pulmonary aspiration, but it is not sensitive, and it is expensive. Clearance of a technetium-99m-radiolabeled meal from the esophagus is documented by scintigraphy. The patient undergoes immediate scanning to document esophageal reflux of labeled material. This procedure may be followed by scanning the next morning to document pulmonary

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aspiration. In a study comparing scintigraphy to other modes of diagnosis, a sensitivity of only 36% was seen; however, the specificity was greater than 88%.85 Other studies have found similar sensitivity values.12,77 The sensitivity of radionuclide scanning for the diagnosis of This may GER in otolaryngology patients was reported to be only 11°/~.60 be, in part, due to the intermittent nature of GER and the short duration of scintigraphic studies leading to its limited sensitivity. Endoscopy

Upper endoscopy is the most specific test for identifying esophageal complications of GER.5,53 Esophagitis may be seen in up to 40% of reflux patients, and Barrett’s metaplasia may be found in 10% to 15% of patients.*l Similar incidence of esophagitis and Barrett’s metaplasia has been seen in asthma patients with reflux.y2Esophagoscopy has limited usefulness in demonstrating a relationship between GERD and atypical symptoms. The severity of esophagitis determined by endoscopy, however, is an important predictor of the response to medical therapy. Esophageal Manometry

Esophageal manometry is used to demonstrate alterations of esophageal peristalsis and lower esophageal sphincter pressures. Mean lower esophageal sphincter pressure in asthmatic patients is significantly lower when compared with age-matched controls.y1The sensitivity of this test, Nonspecific esophageal motility however, was found to be only 33?’0.~~ disorders are also common in patients with respiratory complications of GERD, which can be diagnosed by manometric studies.18 Ambulatory pH Monitoring

Prolonged esophageal pH monitoring is the most reliable test for diagnosing GERD in patients with atypical presentation^.^^, 58 The sensitivity of the test in diagnosing GERD is approximately 90%. In addition, ambulatory monitoring devices permit evaluation of the temporal relationship between reflux episodes and atypical symptoms. Although this procedure is the most reliable test, it is relatively expensive, it is not available at all institutions, and to some patients it may be uncomfortable.68The addition of a pharyngeal probe to the traditional single distal esophageal pH studies has improved diagnostic accuracy of atypical reflux symptoms. Placement of the distal pH probe in both standard and dual pH monitoring systems is 5 cm above the lower esophageal sphincter. Placement of the proximal probe has been less standardized. An electrode placed in the hypopharynx may be affected by the intermittent variations in moisture and dryness normally seen in the hypopharynx.

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This variation may affect the impedance of the electrode resulting in recordings of pseudoreflux events. Therefore placement of the proximal probe below the upper esophageal sphincter may provide more accurate re~ordings.~~ Several parameters may be considered in the diagnosis of pathologic GER. The most valuable discriminator between physiologic and pathologic reflux is the percentage of time that the pH is less than 4. Many studies in normal populations suggest an upper limit of normal of 4.5% to 7.0% with most people using 5% of the total recording time with pH less than 4 from the distal recording site. Normal values for the proximal probe have not yet been established. Several investigators have used 1.1%of the total recording time that the pH was less than 4 as the upper limit of normal for the proximal probe. One unique measurement that can be obtained from pH recordings that may have its greatest value in the diagnosis of atypical reflux symptoms is the symptom index. This value can be calculated by determining the number of times a symptom is reported and is associated with a reflux event compared to the total number of times the symptom is reported regardless of its association with a reflux event. This calculation is a statistical attempt to define the correlation between intermittent, atypical symptoms and reflux. This method statistically compares esophageal pH data temporally related to symptoms with pH data recorded during symptom-free periods. An example of a pH tracing is shown in Figure 4. Wiener et a P 3used this index to determine whether certain chest symptoms should be considered as related to GER. They reported that if the chest symptoms and the acid reflux episode occurred together less than 25% of the time or more than 75% of the time, the causal association is considered to be low and high. These symptom indexes did not, however, take into account the importance of the total number of chest symptom episodes. That is, a single episode of chest discomfort associated with GER would yield a 100% symptom index. Likewise, 20 epi-

Wheeze 15cm ch 2

86: 2-

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sodes of chest pain associated with GER would also result in a symptom index of 100%. All patients with suspected respiratory complications of GER should be questioned about typical and atypical reflux symptoms. Specifically, patients should be asked if their pulmonary symptoms worsen after meals or when lying down. It is helpful to determine if the patient uses pulmonary medication, such as an inhaler, after eating meals or when experiencing any typical reflux symptoms. Patients may also notice that they become short of breath or experience wheezing or coughing at the same time when they experience heartburn or acid regurgitation. If the history is consistent with GER, a trial of aggressive antisecretory therapy should be initiated without any additional diagnostic studies. In patients who achieve a partial response or fail to respond to empiric therapy, a diagnostic workup should be initiated. Upper endoscopy should be the initial procedure done in patients with symptoms consistent with complicated GERD, such as Barrett's esophagus, peptic strictures, and esophagitis. In patients whose presentation is primarily atypical, the preferred initial diagnostic test is the 24-hour ambulatory pH monitor. Whether or not patients with confirmed pulmonary-related GER should undergo an upper endoscopy for the evaluation of Barrett's esophagus, which can exist in these patients even in the absence of typical symptoms of GER, has not been established. THERAPY

Therapy for patients with pulmonary complications of GERD is similar to that for uncomplicated GERD.83Phase 1 therapy consists of dietary alterations, including avoiding fatty meals, chocolate, alcohol, and cigarette smoking; substituting more frequent smaller meals for larger meals; avoiding eating for several hours before lying down; and elevating the upper body during sleep. Phase 2 therapy involves the addition of antisecretory therapy or prokinetic agents. The role of the proton-pump inhibitor, such as omeprazole or lansoprazole, remains to be established. A double-blinded, randomized, controlled trial comparing five different maintenance therapies for reflux esophagitis was conducted on 175 adult patients with endoscopic evidence of esophagitis.Io6 Maintaining symptomatic remission and endoscopic evidence of reflux esophagitis was more effective with omeprazole alone or in combination with the prokinetic agent, cisapride, than ranitidine or cisapride alone. Further, the combination of omeprazole and cisapride was more effective than ranitidine plus cisapride.'06The use of combination therapy in the initial treatment or in the maintenance of remission in patients with typical or atypical symptoms of reflux warrants further study. As discussed earlier, proton-pump inhibitor therapy is promising for the treatment of the respiratory complications of GER. Frequently a higher than standard dose is required for symptomatic improvement. Treatment of the atypical symptoms of GER, especially asthma, frequently requires

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several months of therapy before a therapeutic response is seen. Therefore medical therapy should not be judged as a failure until high-dose antisecretory therapy has been used for at least 4 to 6 months. Because patients with normal proximal and distal esophageal pH results do not respond to antireflux therapy, patients who did not respond to therapy should have an ambulatory pH study to determine the presence or absence of reflux. pH studies may also be useful in those patients who are beginning to respond to therapy, and there is a suspicion that some degree of reflux remains despite the use of antireflux medications. In these cases, the pH study can be used to titrate the medication doses to the elimination of intraesophageal acidification. Finally, phase 3 therapy involves antireflux surgery. Respiratory complications of GERD may require long-term aggressive medical therapy because these complaints may be slow to resolve. The role of antireflux surgery in treating asthmatics with GERD needs further study. In contrast to treating typical gastrointestinal symptoms of GER, treatment of atypical manifestations most often begins with phase 2 therapy. Studies with limited numbers of patients show benefit for asthmatics when medical management has failed. Patients who fail to respond to medical therapy when the 24-hour pH studies are normal are unlikely to respond to antireflux surgery. Optimal surgical candidates include those with normal esophageal motility and a low lower esophageal sphincter pressure.16 Perhaps success of high-dose proton-pump inhibition will be a more valid indicator of when to proceed with antireflux surgery. Antireflux surgery may be a more cost-effective treatment than long-term, high-dose proton-pump inhibitor therapy. Minimal information, however, is available concerning long-term efficacy of fundoplication therapy. Before this therapy can be recommended, additional investigations evaluating the efficacy, long-term benefits, and complications of antireflux surgery must be done. Regardless of the type of therapeutic intervention, subjective and objective measures need to be defined and monitored. Patients should monitor their peak expiratory flow rates and asthma symptoms while in therapy. If the patient’s symptoms do not improve with acid suppression and acid suppression has been documented with a 24-hour pH study, the patient’s pulmonary symptoms are not likely related to GER. If the patient’s pulmonary symptoms and objective measures of peak expiratory flow rates improve with antisecretory therapy, long-term treatment will likely be required. SUMMARY

Further advances in the ability to diagnose GER disease by use of ambulatory pH monitoring have unveiled a host of extraesophageal manifestations of GERD. These include pulmonary symptoms of asthma, recurrent pneumonia, cough or bronchitis, and infant apnea. Many of these symptoms may be the sole presentations of GER in these patients.

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It is important that the clinician is aware of these atypical presentations of GERD. The expanding use of ambulatory pH monitoring is helping to clarify the underlying pathophysiology of these disorders as well as to improve the ability to diagnose the atypical manifestations of GERD. References 1. Allen CJ, Newhouse MT Gastroesophageal reflux and chronic respiratory disease. Am Rev Respir Dis 129:645-647, 1984 2. Bain Wh4, Harrington JW, Thomas LE, et al: Head and neck manifestations of GER. Laryngoscope 9317.5179, 1983 3. Battle WS, Nyhus LM, Bombeck CT Gastroesophageal reflux: Diagnosis and treatment. Ann Surg 177560-565,1973 4. Bauman NM, Sandler AD, Smith RJH Respiratory manifestations of GER disease in pediatric patients. Ann Otol Rhino1 Laryngol 105:23-32, 1996 5. Behar J, Biancani P, Sheahan DG: Evaluation of esophageal tests in the diagnosis of reflux esophagitis. Gastroenterology 71:9-15, 1976 6. Bengtsson U, Sandberg N, Bake B, et al: Gastro-oesophageal reflux and night-time asthma. Lancet 1:1501-1502, 1985 7. Berquist WE, Rachelefsky GS, Kadden M, et al: Gastroesophageal reflux-associated recurrent pneumonia and chronic asthma in children. Pediatrics 68:29-35, 1981 8. Berquist WE, Rachelefsky GS, Rowshan N, et al: Quantitative GER and pulmonary function in asthmatic children and normal adults receiving placebo, theophylline, and metaproterenol sulfate therapy. J Allergy Clin Immunol 73253-258, 1984 9. Campo S, Morini S, Re MA, et al: Esophageal dysmotility and GER in intrinsic asthma. Dig Dis Sci 421184-1188, 1997 10. Castell DO, Wu WC, Ott DJ (eds): Gastro-esophageal Reflux Disease: Pathogenesis, Diagnosis, Therapy. Mount Kisco, NY, Futura Publishing, 1985, p 325. 11. Chen PH, Chang MH, Hsu SC: Gastroesophageal reflux in children with chronic recurrent bronchopulmonary infection. J Pediatr Gastroenterol Nutr 13:1&22, 1991 12. Chemow B, Johnson LF, Janowitz WR, et al: Pulmonary aspiration as a consequence of GER A diagnostic approach. Dig Dis Sci 24:839-844, 1979 13. Christensen J: Pharmacological identification of lower esophageal sphincter. J Clin Invest 49:681491, 1970 14. Crausaz FM, Favez G: Aspiration of solid food particles into lungs of patients with GER and chronic bronchial disease. Chest 92376-378, 1988 15. Davis RS, Larsaen GL, Grunstein MM: Respiratory response to intraesophageal acid infusion in asthmatic children during sleep. J Allergy Clin Immunol 71:393-398, 1983 16. DeMeester TR, Bonavina L, Albertucci M: Nissen fundoplication for GER disease: Evaluation of primary repair in 100 consecutive patients. Ann Surg 204:9-20, 1986 17. DeMeester TR, Bonavina L, Iascone C, et al: Chronic respiratory symptoms and occult GER A prospective clinical study and results of surgical therapy. Arch Surg 211~337-345, 1990 18. DeMeester TR, Wernly JA, Little AG, et al: Technique, indications, and clinical use of 24 hour esophageal pH monitoring. J Thorac Cardiovasc Surg 79:656-670, 1980 19. Denjean A, Herve P, Simonneau G, et al: Effects of acid infusion into the esophagus on airflow obstruction and bronchial hyperreactivity in adult asthmatic patients. Chest 87(suppl):201S-202, 1985 20. Dent J, Doddson J, Friedman RH, et al: Mechanism of GER in recumbent asymptomatic human subjects. J Clin Invest 6525&267,1980 21. Deschner WK, Benjamin SB: Extraesophageal manifestations of GER disease. Am J Gastroenterol 841-5, 1989 22. Dimarino AJ, Cohen S: Effect of an oral beta,-adrenergic agonist on lower esophageal sphincter pressure in normals and in patients with achalasia. Dig Dis Sci 2710631066, 1982

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Address reprint requests to Michele A. Young, MD University of Arizona Carl T. Hayden Veterans Administration Medical Center Gastrointestinal Motility Laboratory Division of Gastroenterology and Hepatology 650 East Indian School Road Phoenix, AZ 85012