Review article: extraoesophageal manifestations of gastro-oesophageal reflux disease

Transcription

1 Aliment Pharmacol Ther 2005; 22 (Suppl. 1): Review article: extraoesophageal manifestations of gastro-oesophageal reflux disease J. E. RICHTER Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA Accepted for publication 29 April 2005 SUMMARY Although recent studies suggest that gastro-oesophageal reflux disease may frequently contribute to ear, nose and throat and respiratory diseases, the cause-andeffect relationship is far from proven. The review will address this controversial topic emphasizing recent literature raising concerns about the credibility of this association and our tests to make this diagnosis. The author believes these extraoesophageal symptoms suspected to be secondary to gastro-oesophageal reflux disease are an unresolved issue, but selective use of aggressive proton-pump inhibitor therapeutic trials may help to resolve this problem in our individual patients. INTRODUCTION Over the last 20 years, a revival has occurred based on evolving data and sometimes overzealous enthusiasm suggesting that gastro-oesophageal reflux disease (GERD) causes a wide spectrum of non-oesophageal conditions including non-cardiac chest pain, asthma, chronic cough, hoarseness, posterior laryngitis, pulmonary fibrosis and even dental erosions. 1 If true, these extraoesophageal manifestations of GERD combined with classic reflux disease (heartburn, acid regurgitation, peptic strictures and Barrett s oesophagus) may well affect 40 50% of the Western population, at sometime in their life. However, the pendulum has begun to swing in the opposite direction recently as we begin to realize that tests of association do not prove causality, ph testing does not accurately categorize these patients, and placebo-controlled studies with highdose proton-pump inhibitors (PPIs) have very inconsistent results in this group of patients. This review, emphasizing the more recent medical literature, will Correspondence to: Prof. Dr J. E. Richter, Department of Medicine, Temple University School of Medicine, 3401 North Broad Street, Philadelphia, PA 19140, USA. jrichter@temple.edu expand on these points and the unresolved scientific challenge of the extraoesophageal manifestations of GERD. PREVALENCE AND CLINICAL OVERVIEW Population-based surveys from the Westernized countries have helped define the prevalence of extraoesophageal complaints possibly because of GERD in the general population. Using a validated self-report questionnaire of 2200 residents from Olmsted County, Minnesota (home of the Mayo Clinic), Locke et al. found that pneumonia and non-cardiac chest pain (23.6% and 23.1% respectively) were the most common extraoesophageal complaints associated with GERD, followed by hoarseness (14.8%), bronchitis (14.0%), asthma (9.3%) and globus (7.0%). 2 Overall, 80% of subjects with weekly heartburn had at least one extraoesophageal symptom, compared with 49% of responders without heartburn or acid regurgitation. El-Serag and Sonnenberg 3 used a national veteran (VA) hospital database to compare comorbid occurrences of sinus, laryngeal and pulmonary diseases in patients with and without reflux oesophagitis, evaluating a case population of patients discharged from VA s hospitals 70 Ó 2005 Blackwell Publishing Ltd

2 REVIEW: GERD NON-GI MANIFESTATIONS 71 from 1981 to Patients with erosive oesophagitis and oesophageal strictures were at a higher risk, compared with hospital controls, of having a variety of extraoesophageal complications especially pneumonia, pulmonary fibrosis and bronchial asthma. Overall, 17% of patients with oesophagitis had an extraoesophageal disease associated with their GERD. Finally, the prospective ProGERD study from Europe involving 6215 patients with heartburn supports the findings from the United States. 4 The prevalence of extraoesophageal symptoms was 32.8%, being slightly more common in patients with erosive oesophagitis (34.9%) than in patients with non-erosive disease (30.5%). Chest pain was the most frequent complaint (14.5%) followed by chronic cough (13%), laryngeal disorders (10.4%) and asthma (4.8%). Epidemiological studies help to define associations and the likelihood (risk) of these occurrences. However, association does not prove disease causality, which is the key for treating our patients. This can only be resolved if there is sound physiological rationale for these associations, diagnostic tests help to discriminate disease groups, and most importantly treatment with active medications predictably improve the disease better than a placebo. EAR, NOSE AND THROAT DISEASES Nearly 10% of patients presenting to ear, nose and throat (ENT) doctors may have symptoms attributed to GERD. 1 Hoarseness presumably caused by acid reflux occurs in an estimated 10% of all cases seen by ENT doctors. Chronic laryngitis and persistent sore throat are associated with acid reflux in as many as 60% of patients. Globus sensation, a feeling of a lump in the throat more prominent between meals and generally disappearing at night, may be caused by GERD in 25 50% of cases. Finally, laryngeal cancer has been associated with GERD in several case series. The association with GERD and these complaints is made by the ENT specialists after finding changes consistent with reflux laryngitis on laryngeal examination. These patients are told they have reflux laryngitis, ENT reflux or laryngopharyngeal reflux which seems to be epidemic in some of these specialists practices. Closer inspection however, suggests that these patients are atypical candidates for a GERD diagnosis. For example, the classic features of GERD are often lacking. Nearly all series report that <50% of complainers have heartburn or acid regurgitation. Furthermore, endoscopic evidence of oesophagitis is low in the range of 10 30% and when present, usually mild. 1 Complicating the situation, up to 50% of patients with laryngoscopic signs suggestive of GERD do not have abnormal oesophageal ph tests or respond to aggressive acid suppression. These inconsistencies increase health care costs through many unnecessary tests and produce a group of dissatisfied and confused patients. Our ENT colleagues argue that either the degree of acid reflux is inconsistently controlled on a daily basis or other agents in the gastric refluxate, such as bile acids, are responsible for the ENT complaints and signs. On the contrary, gastroenterologists counter that irritating causes other than GERD are the culprit with the ENT signs of reflux laryngitis being non-specific and over sensitive. The controversies in this area are well summarized in a recent article by Vaezi et al. 5 PATHOPHYSIOLOGY Animal studies consistently show that the combination of acid and pepsin, applied for several minutes two to three times a week, causes injury to the larynx. 6 Based on these studies without human data, several ENT groups propose that injury to the human larynx does not require large volumes or continuous reflux of gastric contents, especially if the vocal cords are previously injured by viral infection, smoking, alcohol, or voice abuse. 6 An alternative hypothesis with even less supporting data is that acid reflux into the distal oesophagus triggers a vagally mediated reflex, causing chronic repetitive throat clearing and coughing leading to laryngeal signs and symptoms. If correct, human studies should find a high frequency of abnormal oesophageal ph studies and these ENT patients should respond well to PPI therapy. However, this not being the case, enthusiasts for the concept now counter that persistent symptoms must be secondary to non-acid reflux made worse by PPI therapy. Evolving technology, which assesses both acid and non-acid reflux, will soon help answer this question. At this time, we do know that Bilitec monitoring, which measures the reflux of bilirubin as a surrogate marker of bile, finds that PPIs reduce both acid and bile reflux simultaneously. 7 Multichannel, intraluminal impedance allows the accurate measurements of fluids and gases, independent of ph, in the oesophagus. 8 Preliminary 24 h ph testing combined with impedance data from our

3 72 J. E. RICHTER group finds that ENT patients not responding to b.d. PPI therapy rarely have either oesophageal or pharyngeal reflux of non-acid material. Finally, animal studies do not support a role of non-acid reflux in extraoesophageal ENT complaints. We recently completed a series of studies in the cat model showing that bile constituents, both unconjugated and conjugated bile acids, as well as trypsin did not cause injury to the larynx in the nonacid range of ph 4 7. Similar to previous studies, the most injurious agents were acid and pepsin at ph 1 3, conjugated bile acids augmented this injury. 9 DIAGNOSTIC TESTS Table 1. Ear, nose and throat (ENT) signs in normal volunteers 10 Common signs Interarytenoid bar 70 Arytenoid medial wall erythema 29 Posterior pharyngeal wall cobblestoning 21 Interarytenoid bar erythema 15 Posterior cricoid wall oedema 10 True vocal fold oedema 10 Rare signs True vocal fold lesions 0 False vocal fold erythema/oedema 0/1 Posterior cricoid wall erythema 0 Posterior commissure erythema/oedema 0/1 Posterior pharyngeal wall erythema/oedema 0/0 Prevalence (%) Laryngoscopy Laryngoscopy, either by indirect mirror, flexible or rigid laryngoscope, is usually the first examination received by patients with suspected reflux-related ENT symptoms. The findings reported for reflux laryngitis are a constellation of signs involving the posterior larynx nearest the upper oesophageal sphincter. These include laryngeal oedema and erythema, vocal cord oedema, polyps and granulomas, interarytenoid bar, posterior pharyngeal wall cobblestoning, pseudosulcus vocalis and excessive mucus. 9 However, the specificity of these findings for acid injury is not well studied and their prevalence in a healthy population, exposed to other irritants, is unknown. We recently investigated the baseline prevalence of laryngeal signs attributed to GERD in a group of healthy subjects without heartburn complaints. 10 All subjects completed a questionnaire identifying the presence or absence and severity of heartburn and common ENT symptoms as well as the presence of other potential irritants (i.e. voice abuse, allergies, smoking, postnasal drip). Videotape flexible laryngoscopy was done by a single voice specialist blinded to the details of the questionnaire. To our surprise, 91 of 105 (87%) subjects had at least one abnormal finding, typically attributed to acid reflux. The prevalence of individual laryngeal signs in this healthy population is shown in Table 1. Some have questioned these startling results because we did not exclude silent reflux by ph testing in our volunteers. On the contrary, the most likely origin of these signs was the many other irritants identified by the questionnaire (P value of <0.02 for this association), thus seriously challenging the specificity of current signs for laryngopharyngeal reflux. Other recent studies from the ENT literature further question the reliability of the ENT examination and its poor correlation with symptoms and oesophageal ph test results. A Boston group prospectively analysed 120 videotaped rigid fiberoptic examinations scored by five board certified otolaryngologists blinded to patient information. 11 They found a poor correlation (r ¼ ) between symptoms suggestive of GERD and signs. Furthermore, intraobserver reliability was highly variable on multiple readings (r ¼ ) leading the investigators to state that the laryngeal diagnosis of reflux is highly subjective. Three other groups have failed to find a significant correlation between ENT complaints, laryngoscopic findings and pharyngeal ph results For example, Eubanks et al. 12 studied 222 patients with suspected laryngeal and pulmonary symptoms induced by GER. Only 40% had pharyngeal reflux (one or more ph drops <4) on ph testing and there was no difference in the presence or degree of inflammation at laryngoscopy between patients with and without pharyngeal reflux. In another paper by the same group, 15 only 28% of patients with suspected acid-related ENT symptoms had both abnormal laryngeal examinations and positive pharyngeal ph tests. Importantly, this group, similar to classic reflux patients, did well on PPI therapy or after antireflux surgery. Oesophageal and pharyngeal ph monitoring Overall, only 50% of patients with suspected ENT acidrelated symptoms have abnormal oesophageal ph tests. 7 Some suggest that the presence of pharyngeal acid reflux might better identify these patients. The

4 REVIEW: GERD NON-GI MANIFESTATIONS 73 generally accepted criteria defining a pharyngeal reflux episode include: (i) ph drop to <4 in the pharynx, (ii) pharyngeal ph drop during or immediately after distal oesophageal acid exposure, (iii) ph drop is rapid and sharp, not gradual and (iv) the pharyngeal ph drop should be >2 units. 16 However, artefacts are common therefore, the computer interpretation needs to be carefully reviewed manually, 17 the range of normal is poorly defined (none to 4 ph episodes), 12, 13 and 10 30% of healthy volunteers meet published criteria for abnormal pharyngeal reflux. 18 A recent study by Shaker et al., 19 early advocates of pharyngeal ph testing, casts serious doubts on the discriminatory ability of this technology. They prospectively studied 10 healthy volunteers and two groups of patients with suspected acid-related ENT complaints (12 reflux laryngitis and 15 vasomotor rhinitis). All parameters of pharyngeal acid reflux, such as number of events, duration and distribution, were similar between control subjects and patients. Applying less restrictive ph criteria (i.e. ph drop of 1.0 or 1.5 units rather than 2 units) did not improve on these poor results. Finally, the positive results of pharyngeal ph testing do not predict a more favourable response to antireflux therapy. 6, 20, 21 For example, Ulualp et al. 20 reported that the degree of symptom improvement in 19 of 27 patients exhibiting pharyngeal reflux episodes was similar to the remaining eight patients not having pharyngeal reflux. The accumulating data seriously questions the clinical usefulness of pharyngeal ph monitoring in evaluating patients with suspected acid-related ENT complaints. In fact, we stopped performing oesophageal ph testing as an initial evaluation in these patients. Rather, we reserve this test for patients with persistent symptoms after several months on high-dose PPIs. In this situation, oesophageal and sometimes pharyngeal ph monitoring is performed with the patient on medication and the results are rarely positive (<3%). 22 TREATMENT Uncontrolled studies suggest that % of patients who have suspected acid-related ENT symptoms improve on aggressive antireflux therapy. 6 In these studies, the drug regimen usually was a single- or double-dose PPI for 6 24 weeks. As shown in Table 2, placebo-controlled studies do not share this enthusiasm. 21, In the only favourable study by El-Serag Table 2. Medical antireflux treatment of reflux laryngitis: placebo-controlled studies Improvement Author N Design Treatment Symptoms Laryngoscopic Comments Havas et al Double-blind parallel Lansoprazole 30 mg b.d. 3 months L: 35%; P: 33% L: 43%; P: 54% Screened 100 patients to enrol 15 El-Serag et al Double-blind parallel Lansoprazole 30 mg b.d. 3 months L: 50%; P: 10%* L: 58%; P: 30%** No a priori predictors of response Noordzij et al Double-blind parallel Omeprazole 40 mg b.d. 2 months O: 48%; P: 19% O: NC; P: NC Mild hoarseness and throat clearing better with omeprazole Eherer et al Double-blind crossover Pantoprazole 40 mg b.d. 3 months Panto: 43%; P: 41% Panto: N.S.; P: N.S. Patients on placebo did as well as pantoprazole Vaezi et al Double-blind parallel Esomerprazole 40 mg b.d. 4 months Eso: 42%; P: 46% Eso: N.S.; P: N.S. Enrolled patients had either no or minimal classic GER symptoms NC, no significant change across groups; N.S., no significant difference between groups but both improved; GER, gastro-oesophageal reflux. *P ¼ 0.04; **P ¼ 0.12.

5 74 J. E. RICHTER et al., patients received lansoprazole 30 mg b.d. or matching placebo for 3 months. Six patients in the lansoprazole group (50%) and only one (10%) patient in the placebo group achieved a complete symptomatic response (P ¼ 0.04). Among the symptom responders, only one patient had complete resolution of abnormal laryngeal signs, three had partial improvement and three had no change. Apart from receiving lansoprazole, there was no significant difference between responders and non-responders in GERD symptoms, erosive oesophagitis, ph tests, or laryngeal symptoms and signs. A similarly designed Australian study 24 of 15 patients receiving lansoprazole 30 mg b.d. or placebo for 12 weeks had the opposite results finding no improvement of symptoms or ENT findings over the study duration. The other two studies 21, 25 suggest that the natural history of reflux-associated laryngitis is to improve over time when the patients were treated with either active drug (omeprazole 40 mg b.d. or pantoprazole 40 mg b.d.) or placebo over 2 3 months. Possibly the PPIs had an enhancing effect on the relief of acute symptoms 25 and throat clearing, 21 but the overall effects are not striking and the value of long-term treatment over placebo appears to have been greatly overestimated in previous uncontrolled studies. A recent large double-blind parallel study 26 presented at the plenary session of the Digestive Diseases Week 2004, confirms these previous smaller studies and seriously questions the concept of silent refluxers and oesophageal testing. All patients were entered by ENT specialists after careful high fidelity laryngoscopic examinations which confirmed the presence of reflux laryngitis based on prestudy criteria developed by these doctorss. About 145 patients were randomized in a 2:1 ratio to 16 week treatment with esomerprazole 40 mg twice daily or matched placebo. Over half the patients had no classic symptoms of GERD, while the rest had heartburn less than once a week. Demographic and baseline primary symptom distribution was similar for both groups: throat clearing (50%), hoarseness (20%), cough (13%), globus (9%) and sore throat (8%). Fourteen (15%) PPI and eight (16%) placebo-treated patients reported resolution of their primary suspected acid-related ENT symptom (P ¼ 0.8). Partial symptom relief was also similar for both groups (Table 2). Improvement in laryngeal signs over time was similar across groups (P ¼ 0.9). Despite meticulous scoring of the ENT examination and poststudy review and regrading, less than one-quarter of the patients had abnormal ph test results (distal 29%, proximal 9%, pharyngeal 15%) and the presence of laryngeal signs and symptoms did not correlate with abnormal test results. 27 To date, a total of 214 patients with suspected acidrelated ENT complaints have been studied in placebocontrolled studies. The accumulating data casts serious doubts that either the ENT examination or ph testing can accurately define the subset of patients who will improve with PPI therapy. Rather, the treatment response is unpredictable with some patients having an acid injury and others just getting better over time. Furthermore, the concept that most patients with this syndrome have silent reflux is no longer tenable. 26 Future placebo-controlled parallel studies should focus on the subset of patients with suspected acid-related ENT symptoms who have frequent heartburn and/or associated oesophagitis; a possible more homogeneous subset with an acid aetiology. RESPIRATORY DISEASES Although GERD has become increasingly recognized as a potential cause of respiratory symptoms, the pulmonary community has not embraced this disease association-like their ENT colleagues. This group understands that association does not prove causality and believes that three criteria must be met to solidify the cause-andeffect relationship. 25 First, patients with GERD should have a higher prevalence of pulmonary diseases than patients without GERD. Secondly, pathophysiological mechanisms should logically explain the disease interaction. Thirdly, if GERD contributes to pulmonary symptoms, then antireflux therapy should improve or even resolve the pulmonary process in most patients. As suggested in the clinical overview, the first criteria have been met although results are inconsistent. Pathological mechanisms in both animal and human studies link the interactions between the diseases (see below). However, neither the surgical or medical literature allows one to confidently define and identify subset of patients most likely to benefit from aggressive antireflux therapy. CLINICAL SYNDROMES Asthma The GERD is often present in asthmatics with a wide prevalence between 34 and 89%. 28 Estimates vary

6 REVIEW: GERD NON-GI MANIFESTATIONS 75 depending upon the group of patients studied and how acid reflux was defined (e.g. symptoms or 24 h ph monitoring), being highest in specialized centres dealing with complicated asthmatics and studies defining disease by ph testing. Reflux symptoms are silent in 24 65% of asthmatics studied with ph testing. 29, 30 The clinical history may suggest the diagnosis, especially in patients with adult onset asthma, asthma made worse with meals, exercise or supine position, nocturnal asthma, or difficultto-manage asthma. The latter scenario has the most clinical support and represents a group where testing and 29, 31 treatment might have its greatest impact. Cough The GERD is the third most common cause of chronic cough after postnasal drip and cough variant asthma, with a prevalence ranging from 10 to 25%. 32 Because the act of coughing can provoke GER events, not adequately treating coexisting causes of cough can perpetuate a cough reflux cycle. 33 GERD-related cough occurs predominantly in the day, is non-productive, long-standing, and the majority of the patients recall its onset after an upper respiratory tract infection. 33 Between 43 and 73% of patients with suspected GERD-related cough have no reflux symptoms. 32 identifying several different potential mechanisms. 28 First, a vagally mediated reflex because the tracheobronchial tree and oesophagus share embryonic foregut origin as well as autonomic innervation through the vagus nerve. In the reflex theory, stimulation of acidsensitive receptors by oesophageal reflux activates a vagal response to the lungs causing bronchoconstriction. Bronchoconstriction may, in fact, occur in all individuals as a normal protective mechanism when acid enters the oesophagus. 36 Peak expiratory flow rates return to normal after acid is cleared from the oesophagus, although they do so more slowly in asthmatics. 37 Secondly, the reflux theory indicts the microaspiration of gastric contents into the bronchial tree, which causes direct irritation of the respiratory epithelium and stimulates inflammatory mediators. This mechanism causes the greatest bronchoconstrictive airway changes and is consistently demonstrated in both animal 38 and human 39 studies. Thirdly, oesophageal reflux may cause neural enhancement of bronchial reactivity by increasing bronchomotor responsiveness to other stimuli (i.e. methycholine, isocapnic hyperventilation, cat dander). Similar mechanisms are proposed for acid-induced cough, although with this complaint, an oesophageal-bronchial reflex has the greatest amount of scientific support. 32 Idiopathic pulmonary fibrosis Repeated episodes of gastric aspiration may provoke interstitial fibrosis. In an early study of GERD among subjects with pulmonary fibrosis, both hiatal hernia and GERD were found more frequently among those with pulmonary fibrosis compared with controls. 34 Another recent study found that 90% of consecutive biopsyproven patients with idiopathic pulmonary fibrosis had GER by dual probe ph testing. 35 GERD likely contributes to pulmonary fibrosis among patients with scleroderma, who often have severe reflux disease secondary to low lower oesophageal sphincter (LES) pressure and poor oesophageal motility. The poor outcome of interstitial pulmonary fibrosis patients requires that all receive a careful evaluation for GERD and aggressive treatment if found. PATHOPHYSIOLOGY The pathophysiological link of GERD to respiratory disease is based upon animal and human evidence DIAGNOSTIC TESTS Unlike the ENT syndromes, a simple diagnostic test even with low specificity is not available to suggest that pulmonary complaints are related to GERD. Clinical clues may be helpful and GERD should be considered in all patients with intractable asthma or persistent coughing not responding to antibiotics, antihistamines and asthma medications. Except in a VA hospital study, 40 the yield of endoscopy is low. Oesophageal ph testing is the best study to define an association between diseases, but despite some overzealous advocates, 41 this test does not define causality. Only aggressive antireflux therapy with marked symptom improvement or resolution can resolve this issue. This was recently confirmed in an important study by Ours et al. from my laboratory. 42 After extensive testing and empirical treatments to exclude postnasal drip, asthma and other non-gerd causes of cough, 23 patients were identified. Of these patients, 17 had a positive 24 h ph test, but only six (35%) showed a marked improvement or resolution of their cough during omeprazole treatment

7 76 J. E. RICHTER (40 mg b.d. for 2 weeks then slow taper). On the contrary, a negative ph test was specific as none of these six patients improved with high-dose omeprazole treatment. Overall, an empirical PPI trial was three- to fivefold less costly than initial oesophageal testing. I have now used this approach, most recently substituting esomeprazole 40 mg b.d. for 2 weeks, in over 75 patients with cough with approximately 25% responding dramatically and doing well long-term. In the nonresponders, a 24 h ph test on medication rarely (<3%) finds abnormal GER. 22 TREATMENT Treatment trials in pulmonary patients with suspected GERD have provided little insight into a causal relationship for these two conditions. An extensive review of eight randomized, placebo-controlled clinical trials found that treatment of GERD symptoms was associated with improvement of asthma symptoms in over 60% of patients, may reduce the need for asthma medication, but objective improvement of pulmonary function tests was observed in <25% of patients. 43 On the contrary, a more recent Cochrane Review of 12 randomizedcontrolled trials failed to find any overall improvement in asthma following treatment of GERD. 44 They speculated that subgroups of patients may gain benefit, but it appears difficult to predict responders. Recent treatment trials of patients with GERD and asthma are summarized in Table 3. One uncontrolled study found that rabeprazole 20 mg b.d. for 8 weeks improved peak expiratory flow rates in eight of 21 asthmatics with positive ph tests. Predictors of a good response to PPI therapy included frequent reflux symptoms and non-steroid-dependent asthma. 45 In contrast, a large randomized placebo-controlled study of 173 patients with moderate-to-severe asthma found that lansoprazole 30 mg b.d. for 24 weeks improved asthmatic patients perception of well-being and reduced asthma attacks, especially in the post hoc analysis of the more difficult to control asthmatics. 46 In one of only two studies directly comparing medical and surgical treatments of GERD and asthma in the same group of patients, Sontag et al. 47 found that antireflux surgery, but not medical treatment, over at least 2 years of follow-up, significantly improved asthma symptoms and overall clinical status, but had only minimal effect on pulmonary function, asthma medication used or survival. Unfortunately, the medical regimen consisted of ranitidine 150 mg t.d.s. and not a PPI. Finally, there is an interesting report of a consecutive case series of 46 paediatric asthmatic patients who underwent oesophageal ph testing. 48 Of the 27 children with abnormal ph tests, 18 were treated medically (PPIs and prokinetics) and nine underwent antireflux surgery. Of the 19 patients with normal ph tests, eight underwent empirical aggressive antireflux medical treatment and the remaining 11 children served as controls. All 27 children with GERD undergoing treatment had a significant reduction in the use of short- and long-acting bronchodilators as well as inhaled steroids, while only two children (25%) without Table 3. Recent medical treatment trials for GERD-related asthma Author N Study design Treatment Duration Asthma outcome Tsugeno et al GERD+; 28 GERD) Littner et al Double-blind placebo controlled Sontag et al Randomized study (24 control, 22 medical, 16 surgery) Khoshoo et al (27 GERD+, Case series 19 GERD)) Cohort controlled study Rabeprazole 20 mg 8 weeks GERD+, eight of 21 improved PEF > 20%; GERD), zero of 28 Lansoprazole 30 mg b.d. 24 weeks Post hoc analysis: difficult to control asthmatics had QOL and fl number of asthma attacks Ranitidine 150 mg t.d.s or Nissen fundoplication PPI/prokinetic or Nissen fundoplication *P ¼ GERD, gastro-oesophageal reflux disease; PPI, proton-pump inhibitor; QOL, quality of life; PEF, peak expiratory flow. 2 years Marked improvement/cure of asthma* (surgery: 75%, medical: 10%, control: 4%) 1 year GERD+, 100% fl steroids or bronchodilators; GERD), 25% medical; )GERD, 0% controls

8 REVIEW: GERD NON-GI MANIFESTATIONS 77 GERD showed significant reduction in their asthma medications after medical treatment and none of the untreated control children. The data for treating possible GERD-related cough continues to be characterized by over enthusiasm based on uncontrolled trials and a few less enthusiastic placebo-controlled studies. For example, Poe and Kalloy 49 recently observed that 75% of their 56 patients improved with a single-dose PPI, while the remainder responded when metoclopramide or cisapride was added. A surgical series 50 found that among 21 coughers with GER not responding to aggressive treatment with PPIs, histamine-2 receptor antagonists (H 2 RAs) and prokinetics, 76% had considerable improvement and 62% complete resolution of their cough after antireflux surgery. Unfortunately, this was an observational case series with no controls and there was no documentation of acid control by repeat ph testing on PPIs before surgery. In the two placebocontrolled studies, the predictability of PPI therapy was less than encouraging. As previously discussed, Ours et al. 42 found that 35% of coughers with positive ph tests had resolution of their complaints after 2 weeks of omeprazole 40 mg b.d. compared with 0% response in the placebo control. Kiljander et al. 51 performed a double-blind placebo crossover study in 21 patients with chronic cough and positive oesophageal ph tests. Patients received omeprazole 40 mg a day or placebo for 8 weeks, then after a 2-week washout period were crossed over to the alternate treatment. In the 12 patients receiving placebo followed by omeprazole, cough significantly improved (P ¼ 0.02) on active drug. In nine patients receiving omeprazole in the first period, improvement in cough reached statistical significance only after cessation of omeprazole. UNRESOLVED SCIENTIFIC CHALLENGES The unresolved scientific challenges in the diagnosis and treatment of extraoesophageal GERD are summarized by the pyramid shown in Figure 1. The presence of erosive oesophagitis is the foundation of our treatment strategies for GERD. Oesophagitis has excellent specificity for reflux disease and heartburn; therefore placebo-controlled trials with PPIs have response rates exceeding 85 95%. 1 On the contrary, non-erosive GERD, intuitively a milder disease because visual oesophageal damage is absent, only responds in 60 80% of cases. Drug efficacy is not the issue; rather, Figure 1. The reflux pyramid. Response to acid suppression and true prevalence of gastro-oesophageal reflux (GER) is best at the base of the pyramid. More proximally, the true cause-and-effect relationship with acid reflux diminishes as well as the efficacy of powerful acid suppressive medications. despite the presence of classic reflux symptoms, some of these patients have factors other than acid accounting for their complaints. This complex relationship between symptoms, presence of GERD and the possible causal relationship is further compounded as one goes up the pyramid with the extraoesophageal presentations of GERD. This is especially true in the ENT and respiratory diseases. Oesophageal ph testing only confirms an association between acid reflux and these diseases, but does not allow resolution of the issue. Rather, aggressive therapeutic trials, usually with PPIs or surgery, must be used. Empirical drug trials to identify patients with true GERD-related extraoesophageal complaints are acceptable in clinical practice, but impractical for large clinical trials of drug efficacy. Reliable predictors of treatment response are needed; unfortunately, these have not been identified. Therefore, we have little means of enriching our study population with patients who have true GERD-related extraoesophageal symptoms. This key issue probably accounts for the variable treatment results seen with both aggressive medical and surgical antireflux regimens, making scientific evidence-based algorithms for treating these patients very difficult. CONCLUSIONS The relationship between GERD and extraoesophageal symptoms is complex. For the reasons and data

9 78 J. E. RICHTER High clinical suspicion and/or classic GOR symptoms Low clinical suspicion of GORD PPI BID 24 h ph test Improved No improvement Normal Abnormal Taper treatment ph testing on PPI Seek another Dx BID PPI Trial No recurrence Observe Recurrence Maintenance Therapy Normal Not GORD Abnormal Increase PPI dose Figure 2. Algorithm for the diagnosis and treatment of extraoesophageal presentations of gastro-oesophageal reflux disease (GERD). reviewed, my approach centres around a therapeutic trial with a PPI b.d. for 3 4 months (Figure 2), after excluding other factors which may be causing these symptoms. An initial therapeutic trial circumvents problems with ph testing, is more acceptable to the patient and allows a cause-and-effect relationship to be proven. If symptoms improve or resolve, I attempt step down therapy over 3 6 months. I have little concern about a placebo response, because the key issue is symptom relief only. Patients not responding to the PPI trial, undergo 24 h ph testing on medication. These patients are not tested off medication because the question is not whether they have GERD, but rather do they have good acid control to maximize the chance of resolving acid-related symptoms. A single probe in the distal oesophagus showing good acid control (<3 to 4%) over 24 h is more than adequate to define this issue. I do not find gastric or more proximal oesophageal probes helpful. If acid reflux is well controlled then I am confident GER is not the cause of symptoms. In these patients, our experience with Bilitec and impedance testing do not support the theory of non-acid reflux. In patients with unusual symptoms (i.e. globus, sore throat, burning tongue, breathlessness) and no heartburn, I go directly to oesophageal ph testing. A negative test excludes the diagnosis and attention should address other non-acid aetiologies of their complaints. If abnormal acid reflux is present, then again a therapeutic PPI trial is administered. REFERENCES 1 Richter JE. Extraoesophageal presentations of gastroesophageal reflux disease: an overview. Am J Gastroenterol 2000; 95 (Suppl.): S Locke GR III, Talley NJ, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997; 112: El-Serag HB, Sonnenberg A. Co-morbid occurrence of laryngeal or pulmonary disease with esophagitis in United States military veterans. Gastroenterology 1997; 113: Jaspersen D, Kulig M, Labenz J, et al. Prevalence of extraoesophageal manifestations in gastroesophageal reflux disease: an analysis based on the ProGERD Study. Aliment Pharmacol Ther 2003; 17: Vaezi MF, Hicks DM, Abelson TI, Richter JE. Laryngeal signs and symptoms and gastroesophageal reflux disease: a critical assessment of cause and effect association. Clin Gastroenterol Hepatol 2003; 1: Koufman JA. The otolaryngologic manifestation of gastroesophageal reflux disease. Laryngoscope 1991; 101: Vaezi MF, Richter JE. Role of acid and duodenogastroesophageal reflux disease. Gastroenterology 1996; 111: Tutuian R, Vela MF, Shay SS, Castell DO. Multichannel intraluminal impedance in esophageal function testing and gastroesophageal reflux monitoring. J Clin Gastroenterol 2003; 37: Adhami T, Goldblum JR, Richter JE, Vaezi MF. The role of gastric and duodenal agents in laryngeal injury: an experimental canine model. Am J Gastroenterol 2004; 99: Hicks DM, Ours TM, Abelson TI, et al. The prevalence of hypopharyngeal findings associated with gastroesophageal reflux in normal volunteers. J Voice 2002; 16: Branski RC, Bhattacharya N, Shapiro J. The reliability of the assessment of endoscopic laryngeal findings associated with laryngopharyngeal reflux disease. Laryngoscope 2002; 112: Eubanks TR, Omelanczak PE, Masonian N, et al. Pharyngeal ph monitoring in 222 patients with suspected laryngeal reflux. J Gastrointest Surg 2001; 5:

10 REVIEW: GERD NON-GI MANIFESTATIONS Noordzij JP, Khidir A, Desper E, et al. Correlation of ph probe measured laryngopharyngeal reflux with symptoms and signs of reflux laryngitis. Laryngoscope 2002; 112: Powitzkey ES, Khaitan L, Richards WO, et al. Symptoms, quality of life, videolaryngoscopy and 24 hour triple probe ph monitoring in patients with typical and extraoesophageal reflex. Ann Otol Rhinol Laryngol 2003; 112: Oelschlagor BK, Eubanks TR, Masonian N, et al. Laryngoscopy and pharyngeal ph are complementary in the diagnosis of gastroesophageal-laryngeal reflux. J Gastrointest Surg 2002; 6: Williams RB, Ali GN, Wallace KI, et al. Esophagopharyngeal acid regurgitation: dual ph monitoring criteria for its detection and insight into mechanisms. Gastroenterology 1999; 117: Wo JM, Jabbar A, Winstead W, et al. Hypopharyngeal ph monitoring artifact in detection of laryngopharyngeal reflux. Dig Dis Sci 2002; 47: Shaker R, Milbroth M, Ren J, et al. Esophagopharyngeal distribution of refluxed gastric acid in patients with reflux laryngitis. Gastroenterology 1995; 109: Shaker R, Bardan E, Gu C, et al. Intrapharyngeal distribution of gastric acid refluxate. Laryngoscope 2003; 113: Ulualp SO, Toohill RJ, Shaker R. Outcome of acid suppressive therapy in patients with posterior laryngitis. Otolaryngol Head Neck Surg 2001; 124: Noordzij JP, Khidr A, Evans BA, et al. Evaluation of omeprazole in the treatment of reflux laryngitis: a prospective, placebo-controlled, randomized, double-blind study. Laryngoscope 2001; 111: Vaezi MF, Charbel S. On-therapy ph monitoring: usually recommended but should we do it? Gastroenterology 2004; A El-Serag HB, Lee P, Buchner A, et al. Lansoprazole treatment of patients with chronic idiopathic laryngitis: a placebo-controlled trial. Am J Gastroenterol 2001; 96: Havas T, Huang S, Levy M, et al. Posterior pharyngolaryngitis. Double-blind randomized placebocontrolled trial of proton pump inhibitor therapy. Aust J Otolaryngol 1999; 3: Eherer AJ, Habermann W, Hammer HF, et al. Effect of pantoprazole on the course of reflux-associated laryngitis: a placebo-controlled double-blind crossover study. Scand J Gastroenterol 2003; 38: Vaezi MF, Richter JE, Stasney R, et al. A randomized doubleblind placebo controlled study of acid suppression for the treatment of suspected laryngopharyngeal reflux. Gastroenterology 2004; 126: A Richter JE, Vaezi MF, Stasney R, et al. Baseline ph measurements for patients with suspected signs and symptoms of reflux laryngitis. Gastroenterology 2004; 126: A Harding SM, Sontag SJ. Asthma and gastroesophageal reflux. Am J Gastroenterol 2000; 95 (Suppl.): Irwin RS, Curley FJ, French CL. Difficult-to-control asthma: contributing factors and outcome of a systematic protocol. Chest 1993; 103: Harding SM, Guzzo MR, Richter JE. The prevalence of gastroesophageal reflux in asthma patients without reflux symptoms. Am J Respir Crit Care Med 2000; 162: Liou A, Grubb JR, Schechtman KB, Hamilos DL. Causative and contributive factors to asthma severity and patterns of medication use in patients seeking specialized asthma care. Chest 2003; 124: Irwin RS, Richter JE. Gastroesophageal reflux and chronic cough. Am J Gastroenterol 2000; 95 (Suppl.): S8 S Irwin RS, Boulet LP, Cloutier MM, et al. Managing cough as a defense mechanism and as a symptom: a consensus panel report of the American College of Chest Physicians. Chest 1998; 114 (Suppl.): 133S 81S. 34 May EE, Dubois JJ, Hamilton GB. Pulmonary fibrosis associated with tracheobronchial aspiration. Chest 1976; 69: Tobin RW, Pope CE, Pellegrini CA, et al. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998; 158: Wright RA, Miller SA, Corsello BE. Acid-induced esophagobronchial cardiac reflex in humans. Gastroenterology 1990; 99: Schan CA, Harding SM, Haile JM, Bradley LA, Richter JE. Gastroesophageal reflux-induced bronchoconstriction: an intraesophageal acid infusion study using state-of-the-art technology. Chest 1994; 106: Tuchman DN, Boyle JT, Pack AI, et al. Comparison of airway responses following tracheal or esophageal acidification in the cat. Gastroenterology 1984; 87: Connelly RJ, Berrisford RG, Jack CI, et al. Simultaneous tracheal and esophageal ph monitoring: investigating reflux-associated asthma. Ann Thorac Surg 1993; 56: Sontag SJ, Schnell TG, Miller TQ, et al. Prevalence of oesophagitis in asthmatics. Gut 1992; 61: Irwin RS, French CL, Curley FJ, et al. Chronic cough due to gastroesophageal reflux. Clinical, diagnostic and pathogenic aspects. Chest 1993; 104: Ours TM, Kavuru MS, Schilz RJ, Richter JE. A prospective evaluation of esophageal testing and a double-blind, randomized study of omeprazole in a diagnostic and therapeutic algorithm for chronic cough. Am J Gastroenterol 1999; 94: Field SK, Sutherland LR. Does medical antireflux treatment improve asthma in asthmatics with gastroesophageal reflux: a critical review of the literature. Chest 1998; 87: Gibson PG, Henry RL, Coughlan JL. Gastrooesophageal reflux treatment for asthma in adults and children. Cochrane Database Syst Rev 2003; 1: no page numbers. 45 Tsugeno H, Mizuno M, Fujik S, et al. A proton-pump inhibitor, rabeprazole, improves ventilatory function in patients with asthma associated with gastroesophageal reflux. Scand J Gastroenterol 2003; 38:

11 80 J. E. RICHTER 46 Littner MR, Ballard ED, Huang B, Samra NK. Lansoprazole for 24 weeks reduced asthma exacerbations and improves quality of life in subjects with symptoms of acid reflux a multicenter, randomized, double-blind, placebo controlled trial. Am J Gastroenterol 2002; 97: S Sontag SJ, O Connell S, Khandelwal S, et al. Asthmatics with gastroesophageal reflux: long term results of a randomized trial of medical and surgical anti-reflux therapies. Am J Gastroenterol 2003; 98: Khoshoo V, Thao L, Haydel RM, et al. Role of gastroesophageal reflux in older children with persistent asthma. Chest 2003; 123: Poe RH, Kalloy MC. Chronic cough and gastroesophageal reflux disease. Experience with specific therapy for diagnosis and treatment. Chest 2003; 123: Novitsky YW, Zawacki JK, Irwin RS, et al. Chronic cough due to gastroesophageal reflux disease. Efficacy of antireflux surgory. Surg Endosc 2002; 16: Kiljander TO, Salomas ERM, Hietanen EK, et al. Chronic cough and gastro-oesophagal reflux: a double-blind placebocontrolled study with omeprazole. Eur Respir J 2000; 16: