Review Open Access
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Feb 16, 2015; 3(2): 102-111
Published online Feb 16, 2015. doi: 10.12998/wjcc.v3.i2.102
Upper aerodigestive tract disorders and gastro-oesophageal reflux disease
Andrea Ciorba, Chiara Bianchini, ENT Department, University of Ferrara and S. Anna University Hospital, 44124 Ferrara, Italy
Michele Zuolo, Carlo Vittorio Feo, Department of Surgery, University of Ferrara and S. Anna University Hospital, 44124 Ferrara, Italy
Author contributions: Ciorba A, Bianchini C and Zuolo M provided the literature search and drafted the manuscript; Feo CV wrote and revised the manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Andrea Ciorba, MD, PhD, ENT Department, University of Ferrara and S. Anna University Hospital, Via Aldo Moro 8, 44124 Ferrara, Italy.
Telephone: +39-532-239745 Fax: +39-532-237447
Received: July 26, 2014
Peer-review started: July 27, 2014
First decision: August 28, 2014
Revised: September 20, 2014
Accepted: October 28, 2014
Article in press: October 29, 2014
Published online: February 16, 2015


A wide variety of symptoms and diseases of the upper aerodigestive tract are associated to gastro-oesophageal reflux disease (GORD). These disorders comprise a large variety of conditions such as asthma, chronic otitis media and sinusitis, chronic cough, and laryngeal disorders including paroxysmal laryngospasm. Laryngo-pharyngeal reflux disease is an extraoesophageal variant of GORD that can affect the larynx and pharynx. Despite numerous research efforts, the diagnosis of laryngopharyngeal reflux often remains elusive, unproven and controversial, and its treatment is then still empiric. Aim of this paper is to review the current literature on upper aerodigestive tract disorders in relation to pathologic gastro-oesophageal reflux, focusing in particular on the pathophysiology base and results of the surgical treatment of GORD.

Key Words: Clinical management, Gastro-oesophageal reflux, Extraoesophageal disease, Upper aerodigestive tract disorders, Etiopathogenesis, Therapy

Core tip: Despite a growing number of clinical evidences, the association between gastro-oesophageal reflux disease (GORD) and extraoesophageal manifestations still derives from uncontrolled studies on small groups of patients. The evidences in the literature to support the proton pump inhibitor treatment of respiratory symptoms associated with GORD, in the absence of typical symptoms of reflux (heartburn and regurgitation), are scanty. A specific diagnostic tool, of respiratory symptoms associated with GORD, is missing even if oesophageal 24-h pH monitoring has been recommended. Large and prospective studies to assess the successful outcome of antireflux therapy, as well as surgical therapy, are still missing.


Gastro-oesophageal reflux disease (GORD) is a recognized cause of oesophageal symptoms (i.e., heartburn, regurgitation, chest pain, and dysphagia) and inflammatory damages such as erosive esophagitis and intestinal metaplasia (i.e., Barrett’s oesophagus). The association between upper airways disease and pathologic gastro-oesophageal reflux was firstly made in 1968, when laryngeal contact ulcers and granulomas were noted to occur in patients suffering from GORD[1,2], although the concept that GORD could have an impact on laryngeal and pharyngeal disorders has been fully developed in the last 30 years. The reported extraoesophageal manifestations of GORD include asthma, chronic cough, laryngeal disorders, chronic sinusitis, otitis media, and postnasal drip[1]. Laryngo-pharyngeal reflux disease (LPRD) is the term suggested by some authors to define GORD beyond the oesophagus up to the laryngeal and pharyngeal level, thus causing extraoesophageal damages[2,3]. Despite a growing number of clinical evidences to support the association between GORD and extraoesophageal disorders[1], presently the majority of reports still derive from uncontrolled studies of small groups of patients[1]. Nonetheless, in most of the published series, it is difficult to establish a firm connection between GORD and upper aerodigestive disorders (even within the laryngopharyngeal areas), since the presence of gastric content in supraoesophageal structures has been always difficult to document[1,2,4].

This article reviews the current available evidence on extra-oesophageal manifestation of GORD, devoting special attention on the pathophysiology base and results of the surgical treatment of GORD, particularly in relation to arodigestive tract disorders.


The PubMed database was searched up to June 2014, for meta-analysis, systematic reviews, randomized controlled trials, and controlled trials. Full text articles were obtained when the title, abstract or keywords suggested that the study could be eligible for this review. The search was carried out independently. The search was restricted to adults, while no language restriction was applied.

The medical subject heading used included “gastroesophageal reflux”, “laryngopharyngeal reflux”, “gastroesophageal reflux ethiopathogenesis”, “extraoesophageal gastroesophageal reflux disease symptoms”, “reflux laryngitis”, “posterior laryngitis”.


GORD is the most common disease of the oeso-phagus, possibly the most frequently faced by the gastroenterologist. Surveys in the United States have shown that it affects about 20% of the population, while about half experiences heartburn as a minimum once in a month, and 5% to 7% of the population have symptoms related to GORD every day[2,5,6].

Also because of the many clinical variables, the true prevalence of GORD among patients with suspected upper aerodigestive disorders secondary to pathologic gastro-oesophageal reflux is difficult to determine accurately, and it varies depending on the population analysed. For instance, in a study by Koufman et al[7], it has been estimated that about 10% of patients presenting to ears, nose and throat (ENT) clinician may have symptoms and/or findings related to GORD. In another study, it has also been reported that about two-thirds of laryngeal and voice disorders had either pathologic gastro-oesophageal reflux as primary cause or as a significant etiological co-factor[8], and that the prevalence of GORD among patients with laryngeal stenosis is 78%, reflux laryngitis 60%, globus sensation 58%, and chronic cough 52%[9,10]. In another survey, symptomatic reflux was diagnosed by pH monitoring in 30% to 60% of adults affected by asthma and chronic cough and nearly 40% of patients had endoscopic signs of esophagitis[2,11]. More recently, a systematic review has demonstrated typical symptoms of GORD in 59% of 10491 patients with asthma[12]. The proportion of asthma patients with GORD remained as high as 51% when more stringent criteria to prove GORD were adopted (i.e., ambulatory 24-h pH monitoring). The average prevalence of asthma in patients with GORD was 4.6% as compared to 3.9% in controls. The overall odds ratio was 5.5 (95%CI: 1.9-15.8) for studies reporting the prevalence of GORD symptoms in patients with asthma and 2.3 (95%CI: 1.8-2.8) for those studies measuring the prevalence of asthma in patients with GORD. Interestingly, two studies that assessed whether GORD precedes asthma gave inconsistent results. The authors concluded that the analysis indicated a significant association between GORD and asthma, but the direction of causality remained undetermined[12].


Upper aerodigestive tract disorders from pathologic gastro-oesophageal reflux appear to be sustained either directly or secondarily. Direct injury can be due to the result of a direct contact of gastric contents with the mucosa of the extra-oesophageal structures. Alternatively, a neurally mediated vagal reflex can be stimulated by the refluxate in the oesophageal body affecting indirectly the bronchopulmonary system, thus triggering cough, bronchial constriction or laryngospasm[6,13]. However, the evidence confirming the mechanisms of injury in LPRD is still inadequate, and in the literature very few laboratory investigations with animal models have substantiated the noxious effects of the refluxate on these anatomic sites by both direct and indirect mechanisms[14,15].

Certainly, microaspiration of gastric contents can occur during gastro-oesophageal reflux episodes[16]. Direct contact of the refluxate with the mucosa of the pharynx and larynx could therefore represent the main mechanism of injury in LPRD. Unlike the distal oesophagus, the airways are not protected by anti-reflux clearance mechanisms or intrinsic mucosal properties. Moreover, it has been shown that a low lower oesophageal sphincter pressure as well as ineffective oesophageal motility may frequently be present in patients affected by GORD with associated respiratory disease (chronic cough, asthma, laryngitis)[17,18]. It is possible that just a single reflux episode above the oesophagus can be responsible of pharyngeal, laryngeal, and respiratory disorders.

The triggering of a vagal reflex has also been proposed as a consequence of the direct aspiration of refluxed acid into the pharynx or upper airways, besides the stimulation of the distal oesophageal mucosal receptors by the refluxed gastric content[17]. When stimulated, airway nociceptors activate protective responses such as cough and bronchospasm. It is also interesting to evidence that the pathways of some oesophageal and airway sensory nerve fibres terminate within the same regions of the central nervous system; thus, connections among oesophageal nociceptors and airway sensory nerves can exacerbate cough and the asthma-like disorders associated with GORD[19]. So, given the common vagal innervations of lungs and oesophagus, it is not surprising that many patients with asthma and chronic cough also have GORD, and that reflux often precipitates respiratory symptoms that are clinically indistinguishable from asthma[2,19].

Also the specific reflux agent or agents responsible for producing otolaryngology symptoms and pharyngo-laryngeal injury are currently debated[20]. Potential candidates include gastric contents (i.e., acid and pepsin) as well as duodenal contents, including both bile acids and the pancreatic enzyme trypsin. Several animal studies suggested an injurious potential for both acid gastric contents and pepsin[2,20,21].


The Montreal evidence-based global consensus, defining GORD and its constituent syndromes, recognized oesophageal syndromes and established an association between GORD and asthma, chronic cough, and laryngitis, while proposed an association with pharyngitis, sinusitis, and otitis media[22]. The Montreal consensus also acknowledged that such extra-oesophageal disorders have a multi-factorial aetiology and pathologic gastro-oesophageal reflux may well be a co-factor rather than a cause. Thus, patients with asthma, chronic cough or laryngitis should firstly be evaluated for causes not related to GORD, considering that extra-oesophageal syndromes rarely occur without concomitant typical symptoms of GORD[22]. However, the diagnosis of GORD as the cause of extra-oesophageal symptoms is very challenging and relies on the following investigations.


Traditionally, otolaryngologists have commonly used an empiric course of double dose of proton pump inhibitors (PPIs) (i.e., PPI trial) to initially diagnose and treat patients with upper aerodigestive tract disorders suspected to be related to GORD, deeming the resolution of symptoms with such a treatment as diagnostic of LPRD[3,5,6,23]. PPIs have been shown to improve asthma outcomes in terms of a significant reduction in the proportion of subjects experiencing respiratory symptoms including dyspnoea, cough, wheeze in randomized controlled trials[24,25], although a recent meta-analysis of 11 randomized trials found only small improvements of the respiratory function in adult patients with asthma, unlikely to provide a real clinical benefit[26]. Another meta-analysis of randomized trials by the Cochrane Collaboration regarding cough control with PPIs in GORD reported that PPIs were not better than placebo to resolve cough in such a patient, although they improved cough scores[27]. Finally, also for suspected GORD-related chronic laryngitis a meta-analysis of randomized trials has demonstrated no advantage of PPIs vs placebo[28]. Therefore, the evidence to support the treatment with PPIs in the absence of typical symptoms (i.e., heartburn and regurgitation) or objective pathologic gastro-oesophageal reflux (i.e., esophagitis on upper endoscopy or positive ambulatory pH monitoring) is scant[29].


The most frequent laryngoscopic findings that have been related to reflux are oedema and erythema: (1) of the arytenoid cartilages mucosa; (2) of the interarytenoid region; and/or (3) of the posterior third of the true vocal folds (i.e., posterior laryngitis). A reflux finding score based on the presence and the severity of at least eight different grades of lesions at laryngoscopy has been proposed by Belafsky et al[30] to improve the diagnostic accuracy. However, laryngoscopy has revealed laryngeal irritation in more than 80% of healthy controls prospectively evaluated[31] and the concordance among ENT physicians for signs of reflux laryngitis is low when blindly evaluated[32]. Thus, a causal relationship between GORD and laryngitis should not be posed relying on laryngoscopy findings alone.

Indeed, upper endoscopy has excellent specificity for the diagnosis of GORD in the presence of erosive esophagitis[33]; however, only one third of patients with symptoms of GORD, and even less following treatment with PPIs, have erosive esophagitis which does not establish per se a causal relationship between GORD and aerodigestive tract disorders[34,35].


This is the only test that can objectively demonstrate the presence of abnormal oesophageal acid exposure, characterize the reflux episodes and determine their association with symptoms. The pH monitoring has high sensitivity and specificity in the presence of erosive esophagitis (both up to 100%); but its sensitivity lowers (about 70%) in patients without erosive esophagitis, although may be increased adopting impedance pH monitoring (up to 90%)[36,37].

The use of dual pH monitoring (with a probe at the level of the upper oesophageal sphincter) has been proposed by some authors to investigate for respiratory symptoms associated with GORD[23,38]. However, this procedure is not universally performed due to the significant practical problems performing pH monitoring in the pharynx[23,38].

Certainly, there is a great variability in the prevalence of abnormal pH monitoring reported in

patients with asthma, chronic cough, and laryngitis[12,39-41]. However, a negative pH monitoring may address the diagnostic investigations toward aerodigestive disorders non-related to GORD, while a positive pH monitoring establishes a diagnosis of GORD, although it does not imply that the latter is the cause of the respiratory symptoms. The temporal association between reflux episodes and respiratory symptoms may be evaluated by the symptom index (SI, i.e., percentage of symptoms preceded by a drop in oesophageal pH below 4.0 within a 5-min time window divided by the total number of symptoms)[42] and the symptom association probability (SAP, i.e., statistical probability with which symptoms and reflux episodes are associated)[43]. The patient must promptly record the symptoms, while the machine should accurately detect the reflux episodes (i.e., drop in oesophageal pH below 4.0) in order to evaluate precisely the temporal association between symptoms (i.e., asthma attacks or cough events) and acid reflux episodes. A positive symptom association is declared if the SI is greater than or equal to 50% (i.e., at least half of the reported symptoms are preceded within a 5-min time window by an intra-oesophageal pH below 4.0) or if the SAP is greater than 95% (i.e., the probability of this association having occurred by chance is less than 5%). Unfortunately, both sensitivity and specificity of symptom association analysis tools is limited and there are no outcome studies to support treatment of extra-oesophageal GORD based on this parameter alone[29]. Recently, Smith et al[39] by using a microphone to record cough concurrently with the pH-impedance recording, to overcome patients not always recording timely their symptoms during pH monitoring, reported 6 to 18 times more coughing than with patient reported cough, and 2 to 3 times more than relying on manometry to suppose when cough possibly occurred. If these data will be confirmed by further studies, the evaluation of the temporal association between reflux episodes and respiratory symptoms will be improved.


Some authors have reported about the possible relationship between asthma and GORD, since a percentage between 30% to 80% of asthmatic patients, have been found to have GORD and/or esophagitis[43-45]. Nonetheless, a cause effect association between GORD and asthma has not been found yet[43-45]. Most of the reports show that GORD medical therapies such as histamine H2 antagonists or PPIs can be effective on asthma outcome[45,46], even if such medications have not been reported to improve asthma symptoms or pulmonary function[43-45].

Finally, on the contrary, few reports have claimed that inhaled b2 agonists and oral corticosteroids, currently used for asthma therapy, may increase oesophageal acid refluxate[2,45-50].


Chronic cough is also believed to be possibly related to GORD as proposed by several studies[51-54]. In fact Harding[44] and Pacheco-Galván et al[49] have reported that both, medical and surgical therapy of pathologic reflux, can improve or even resolve chronic cough in up to 51% to 100% of adult patients. Unfortunately, most of the data available in the literature come from uncontrolled studies with small sample sizes of patients, and evidences about the efficacy of therapy are still lacking. Long term follow-up studies with a large number of patients are missing.


GORD is also considered to be a possible cause of laryngeal disease: it has been suggested that the aetiopathogenetic mechanism underlying laryngeal disorders, such as chronic laryngitis, could be caused by the contact of the acid refluxate with the laryngeal mucosa. Therefore, patients affected by chronic laryngitis who lack anomalies at the laryngoscopic evaluation should be addressed to a pH monitoring and gastroesophageal endoscopy in order to reveal signs of reflux[55-57]. Some authors have already reported that they have successfully treated with PPIs some laryngeal diseases such as chronic laryngitis as well as contact granuloma and acquired subglottic stenosis[58-60]. In the study by El-Serag et al[61], patients treated with PPIs showed efficacious resolution of laryngeal symptoms when compared to a placebo group. Nonetheless, the small amount of patients involved, as well as the limited follow-up, represent the main drawbacks of this and of similar studies[2,49,56,61,62].


Some reports have advocated GORD to have a possible role in the aetiopathogenesis of chronic sinusitis and that medical anti-reflux therapy may be useful for these patients[63]. It has been speculated that GORD may cause sinonasal congestion and alteration of sinusal drainage with consequent inflammation[2,49,64].


Also paroxysmal laryngospasm episodes have been associated by some authors to GORD, and medical anti-reflux therapy with PPIs has been reported to be of benefit for these patients. According to the aetiopatogenetic mechanism indicated by these authors, paroxysmal laryngospasm could be considered as a vagally mediated reflex response of the larynx to acid refluxate, a potentially injurious stimulus[2,49,63,65-67].


To date, there are only few reports indicating GORD as a possible cause of persistent middle ear problems (i.e., otitis media with effusion). Unfortunately studies considering this specific issue, in adults and children, still are scant[68-70].


The diagnosis of LPRD is still very controversial, both in clinical practice and research. Most guidelines and reviews recommend starting the diagnostic work-up and treatment of patients with upper aerodigestive symptoms of GORD with an empiric trial of PPI therapy at a double dose given for at least three months[3,5,6,23]. Traditionally, in clinical practice, otolaryngologists have considered diagnostic of LPRD the resolution of symptoms following such a PPI trial. Failure to respond, on the other hand, would indicate incorrect diagnosis of GORD or inadequate dosing or resistance to the treatment. Nonetheless, in patients who do not respond to the empirical trial, further investigations (e.g., ambulatory 24-h oesophageal pH monitoring) have been recommended[2,3,5,23].


As stated above, PPIs are the main proposed treatment for LPRD. Caution must be used, however, interpreting the available literature, as it is hampered by studies lacking strict inclusion and diagnostic criteria investigating large populations and, consequently, inconclusive meta-analyses. Nonetheless, partial improvement of both symptoms and laryngoscopic signs of laryngitis has been reported with PPI treatment and behavioural changes. Lifestyle modifications comprise the avoidance of heavy and late meals, alcohol consumption, and smoking. Also, to elevate the head of the bed and to reduce the body weight may be beneficial[6]. Most handbooks and reviews suggest a three-month treatment with PPIs at a double dose as the first step in the diagnosis and treatment of patients with upper aerodigestive symptoms attributed to GORD[3,5,6,23]. Patients who do not respond, however, are indeed particularly challenging. Several factors have been suggested to explain refractory cases, such as inadequate dosing or resistance to PPIs, sensitivity to non-acid refluxate, and incorrect diagnosis of GORD. Thus, the dosages of PPIs as well as the frequency of their administration can be increased and pro-motility agents and histamine receptor antagonists may be added. Finally, in patients with signs and symptoms of LPRD despite PPIs treatment, 24-h ambulatory pH monitoring while the patient is on medication may demonstrate persistent acid refluxate due to the lack of acid control[6].

Historical background

In 1956, Rudolph Nissen, a German surgeon, opened the era of modern anti-reflux surgery describing a complete plication of the gastric fundus around the abdominal portion of the esophagus that restored an anti-reflux barrier[71]. The Nissen operation has been modified throughout the years, new valves around the abdominal oesophagus, either complete (360°) or partial (240°-270°) have been described, but the basic principle of the operation remained unchanged: to restore a high pressure zone (HPZ) at the gastro-oesophageal junction[72-80]. In 1991, Dallemagne et al[81] reported the first laparoscopic anti-reflux operation. In the following decade the technique has been adopted worldwide becoming the gold standard for surgical management of GORD.

Indications and technical details

The surgical treatment of GORD is focused on restoring a HPZ at the lower oesophageal sphincter (LOS), while medication aim to modify the pH of the refluxate. Nowadays, this purpose is achieved by a fundoplication performed laparoscopically, which offers excellent results combined with the postoperative advantage of a short hospital stay, minimal discomfort, and fast recovery time as compared to the open (i.e., laparotomic) traditional operation[82-85]. According to the 2010 guidelines of the Society of American Gastrointestinal Endoscopic Surgeons, the surgical operation should be considered in the following situations: (1) failure of medical treatment because of inadequate symptom control, persistent severe regurgitation or disturbing side effects; (2) preference of the surgical treatment despite symptom control on PPIs due to quality of life, refusal of lifelong need for medication or costs of medications; (3) presence of Barrett’s oesophagus or peptic stricture; and (4) extra-oesophageal symptoms such as asthma, hoarseness, cough, and chest pain or aspiration[86].

The surgical literature is full of eponyms of anti-reflux operations that quite often do not even correspond to the operation originally described by the authors[87]. Therefore, it seems very reasonable to go beyond such eponyms, and stress the surgical elements, common to most of these operations, that have been shown to guarantee long term control of reflux for the patient, namely: (1) to reduce the hiatal hernia in the abdomen; (2) to mobilize extensively the oesophagus and gastro-oesophageal junction; (3) to reduce the hiatus; (4) to interrupt the gastro-splenic ligament; (5) to construct a partial or complete fundoplication of adequate length and tightness; and (6) to fix with posterior and coronal stiches the wrap[87].

Results of anti-reflux surgery

Anti-reflux surgery (i.e., fundoplication) has been shown in clinical studies to control GORD symptoms in 93% and 89% of patients after 5 years and 10 years, respectively[82]. Surgical fundoplication restores the LOS competence and improves the oesophageal peristalsis[88]. Of note, due to the restoration of a HPZ, the reflux control is equally effective when the patient is supine or upright[83]. Anti-reflux surgery has been shown to be safe and effective also in elderly patients affected by GORD[84]. In a randomized trial at a Veteran Affairs Cooperative comparing medication to anti-reflux surgery for GORD, patients on medication at 10-year follow-up in the medical therapy group as opposed to the surgical group were 92% and 62%, respectively[89]. The surgical treatment of GORD may, however, expose patients to some morbidity and increased risk of mortality. The most common complication related to anti-reflux surgery is the so called gas-bloating syndrome, affecting 15% to 20% of patients. Recently, a meta-analysis concluded that a partial (240°) fundoplication as compared to a complete (360°) wrap was associated to less postoperative dysphagia and inability to belch in patients undergoing surgical treatment of GORD[90]. A Cochrane review including more than 1200 patients from four randomized trials comparing medical to surgical therapy has demonstrated higher improvements in GORD specific quality of life after surgery, although a meta-analysis of such data was not performed[91]. Symptoms of heartburn, regurgitation, and bloating improved more after surgical fundoplication then with medication, even if small proportion of patients had persistent dysphagia after surgery. Nonetheless, the surgical operation is associated with some risk of complications and the decision to perform a surgical fundoplication needs to be thoroughly discussed with the patient.

Results on respiratory symptoms

The control of respiratory symptoms in patients with GORD undergoing anti-reflux surgery is less predictable. In the era of the open (i.e., laparotomic) surgical operation, objective data regarding the ability of a fundoplication to control respiratory symptoms in patients with GORD were scarce[92,93]. For instance, Pellegrini et al[93] reported the successful results of a complete fundoplication performed in a small group of patients in whom GORD-induced aspiration had been diagnosed. In the past two decades, due to the advent of laparoscopic anti-reflux surgery, the number of patients undergoing fundoplication for GORD has greatly increased[87,94]. Hunter et al[94] reported resolution or improvement of respiratory symptoms in 76 out of 87 patients (87%) undergoing laparoscopic fundoplication. However, outcomes of patients with extra-oesophageal symptoms undergoing anti-reflux surgery are not always predictable. A Veteran Affairs Cooperative study, reported no significant improvement in pulmonary function tests one year after fundoplication, even in those patients presenting abnormal preoperative tests[95]. Analogously, a randomized trial showed that both medical and surgical therapy did not increase significantly the forced expiratory volume in 1 s after 6 mo[96]. Anti-reflux surgery can control extra-oesophageal symptoms in carefully selected patients with GORD, although these patient should be informed that the success rate is lower than in patients with typical symptoms[97]. It is particularly important to carefully evaluate the response of such patients to PPIs, as in patients who do not respond to medications, even in the presence of oesophageal acid exposure demonstrated by pH-monitoring, the results of fundoplication are not effective[98].


Upper aerodigestive tract disorders related to pathologic reflux appear to be a common but controversial disease, with conflicting data on pathophysiology, diagnosis, and treatment. Whereas trends are observed and many clinical practices are accepted widely on the basis of experience, definitive, prospective, and controlled studies are strongly needed[2,6].

Also considering the possible implication of GORD in the development of supra-oesophageal neoplasms, as advocated by several investigators, more efforts are necessary to support the relation between extra-oesophageal disorders and GORD, in terms of prospective randomized trials[2].

A better comprehension of the physiopathological mechanisms of these conditions can help clinicians in the management of such patients. In particular, further large randomized-controlled trials in order to clarify LPRD pathophysiology, as well as to evaluate diagnostic algorithms and treatment approaches could be then particularly useful for the diagnosis and the management these disorders.


P- Reviewer: Dumitrascu DL, Figura N, Nishio K S- Editor: Tian YL L- Editor: A E- Editor: Lu YJ

1.  Hogan WJ, Shaker R. Supraesophageal complications of gastroesophageal reflux. Dis Mon. 2000;46:193-232.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 15]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
2.  Ciorba A, Bianchini C, Pelucchi S, Pastore A. Gastroesophageal reflux and its possible role in the pathogenesis of upper aerodigestive tract disorders. Minerva Gastroenterol Dietol. 2007;53:171-180.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Toohill RJ, Kuhn JC. Role of refluxed acid in pathogenesis of laryngeal disorders. Am J Med. 1997;103:100S-106S.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 107]  [Cited by in F6Publishing: 111]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
4.  Coca-Pelaz A, Rodrigo JP, Paccagnella D, Takes RP, Rinaldo A, Silver CE, Woolgar JA, Hinni ML, Ferlito A. Reflux and aerodigestive tract diseases. Eur Arch Otorhinolaryngol. 2013;270:417-423.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 6]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
5.  Locke GR, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology. 1997;112:1448-1456.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1488]  [Cited by in F6Publishing: 1521]  [Article Influence: 58.5]  [Reference Citation Analysis (0)]
6.  Gupta R, Sataloff RT. Laryngopharyngeal reflux: current concepts and questions. Curr Opin Otolaryngol Head Neck Surg. 2009;17:143-148.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 51]  [Cited by in F6Publishing: 53]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
7.  Koufman JA, Wiener GJ, Wallace CW. Reflux laryngitis and its sequela: the diagnostic role of ambulatory 24-hour monitoring. J Voice. 1988;2:78-79.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 103]  [Cited by in F6Publishing: 103]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
8.  Koufman JA. Gastroesophageal reflux and voice disorders. Diagnosis and treatment of voice disorders. NY: Igaku-Shoin 1995; 161-175.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope. 1991;101:1-78.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  el-Serag HB, Sonnenberg A. Comorbid occurrence of laryngeal or pulmonary disease with esophagitis in United States military veterans. Gastroenterology. 1997;113:755-760.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 236]  [Cited by in F6Publishing: 245]  [Article Influence: 9.4]  [Reference Citation Analysis (0)]
11.  Johanson JF. Epidemiology of esophageal and supraesophageal reflux injuries. Am J Med. 2000;108 Suppl 4a:99S-103S.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 51]  [Cited by in F6Publishing: 50]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
12.  Havemann BD, Henderson CA, El-Serag HB. The association between gastro-oesophageal reflux disease and asthma: a systematic review. Gut. 2007;56:1654-1664.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 186]  [Cited by in F6Publishing: 198]  [Article Influence: 12.4]  [Reference Citation Analysis (0)]
13.  Hogan WJ. Spectrum of supraesophageal complications of gastroesophageal reflux disease. Am J Med. 1997;103:77S-83S.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 20]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
14.  Tuchman DN, Boyle JT, Pack AI, Scwartz J, Kokonos M, Spitzer AR, Cohen S. Comparison of airway responses following tracheal or esophageal acidification in the cat. Gastroenterology. 1984;87:872-881.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Mansfield LE, Hameister HH, Spaulding HS, Smith NJ, Glab N. The role of the vague nerve in airway narrowing caused by intraesophageal hydrochloric acid provocation and esophageal distention. Ann Allergy. 1981;47:431-434.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Eubanks TR, Omelanczuk PE, Maronian N, Hillel A, Pope CE, Pellegrini CA. Pharyngeal pH monitoring in 222 patients with suspected laryngeal reflux. J Gastrointest Surg. 2001;5:183-190; discussion 190-191.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 67]  [Cited by in F6Publishing: 65]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
17.  Fouad YM, Katz PO, Hatlebakk JG, Castell DO. Ineffective esophageal motility: the most common motility abnormality in patients with GERD-associated respiratory symptoms. Am J Gastroenterol. 1999;94:1464-1467.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 146]  [Cited by in F6Publishing: 155]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
18.  Ylitalo R, Ramel S, Hammarlund B, Lindgren E. Prevalence of extraesophageal reflux in patients with symptoms of gastroesophageal reflux. Otolaryngol Head Neck Surg. 2004;131:29-33.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 18]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
19.  Canning BJ, Mazzone SB. Reflex mechanisms in gastroesophageal reflux disease and asthma. Am J Med. 2003;115 Suppl 3A:45S-48S.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 66]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
20.  Vaezi MF. Sensitivity and specificity of reflux-attributed laryngeal lesions: experimental and clinical evidence. Am J Med. 2003;115 Suppl 3A:97S-104S.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 34]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
21.  Stamp DH. Three hypotheses linking bile to carcinogenesis in the gastrointestinal tract: certain bile salts have properties that may be used to complement chemotherapy. Med Hypotheses. 2002;59:398-405.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 49]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
22.  Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101:1900-1920; quiz 1943.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2368]  [Cited by in F6Publishing: 2338]  [Article Influence: 137.5]  [Reference Citation Analysis (1)]
23.  Kahrilas PJ, Ergun GA. Otolaryngologic manifestations of GERD. Ambulatory esophageal pH monitoring: a practical approach and clinical applications. 2nd ed. New York: Igaku-Shoin 1997; 133-148.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Harding SM, Sontag SJ. Asthma and gastroesophageal reflux. Am J Gastroenterol. 2000;95:S23-S32.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 54]  [Cited by in F6Publishing: 56]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
25.  Kiljander TO, Junghard O, Beckman O, Lind T. Effect of esomeprazole 40 mg once or twice daily on asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2010;181:1042-1048.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 93]  [Cited by in F6Publishing: 98]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
26.  Chan WW, Chiou E, Obstein KL, Tignor AS, Whitlock TL. The efficacy of proton pump inhibitors for the treatment of asthma in adults: a meta-analysis. Arch Intern Med. 2011;171:620-629.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 68]  [Article Influence: 5.7]  [Reference Citation Analysis (0)]
27.  Chang AB, Lasserson TJ, Gaffney J, Connor FL, Garske LA. Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults. Cochrane Database Syst Rev. 2011;19:CD004823.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3035]  [Cited by in F6Publishing: 3049]  [Article Influence: 190.6]  [Reference Citation Analysis (0)]
28.  Qadeer MA, Phillips CO, Lopez AR, Steward DL, Noordzij JP, Wo JM, Suurna M, Havas T, Howden CW, Vaezi MF. Proton pump inhibitor therapy for suspected GERD-related chronic laryngitis: a meta-analysis of randomized controlled trials. Am J Gastroenterol. 2006;101:2646-2654.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 208]  [Cited by in F6Publishing: 198]  [Article Influence: 11.6]  [Reference Citation Analysis (0)]
29.  Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013;108:308-328; quiz 329.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1136]  [Cited by in F6Publishing: 1095]  [Article Influence: 109.5]  [Reference Citation Analysis (0)]
30.  Belafsky PC, Postma GN, Koufman JA. The validity and reliability of the reflux finding score (RFS). Laryngoscope. 2001;111:1313-1317.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 702]  [Cited by in F6Publishing: 723]  [Article Influence: 32.9]  [Reference Citation Analysis (1)]
31.  Milstein CF, Charbel S, Hicks DM, Abelson TI, Richter JE, Vaezi MF. Prevalence of laryngeal irritation signs associated with reflux in asymptomatic volunteers: impact of endoscopic technique (rigid vs. flexible laryngoscope). Laryngoscope. 2005;115:2256-2261.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 131]  [Cited by in F6Publishing: 134]  [Article Influence: 7.9]  [Reference Citation Analysis (0)]
32.  Branski RC, Bhattacharyya N, Shapiro J. The reliability of the assessment of endoscopic laryngeal findings associated with laryngopharyngeal reflux disease. Laryngoscope. 2002;112:1019-1024.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 148]  [Cited by in F6Publishing: 154]  [Article Influence: 7.3]  [Reference Citation Analysis (0)]
33.  Lundell LR, Dent J, Bennett JR, Blum AL, Armstrong D, Galmiche JP, Johnson F, Hongo M, Richter JE, Spechler SJ. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut. 1999;45:172-180.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1518]  [Cited by in F6Publishing: 1591]  [Article Influence: 66.3]  [Reference Citation Analysis (1)]
34.  Ronkainen J, Aro P, Storskrubb T, Johansson SE, Lind T, Bolling-Sternevald E, Graffner H, Vieth M, Stolte M, Engstrand L, Talley NJ, Agréus L. High prevalence of gastroesophageal reflux symptoms and esophagitis with or without symptoms in the general adult Swedish population: a Kalixanda study report. Scand J Gastroenterol. 2005;40:275-285.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 315]  [Cited by in F6Publishing: 315]  [Article Influence: 17.5]  [Reference Citation Analysis (0)]
35.  Gralnek IM, Dulai GS, Fennerty MB, Spiegel BM. Esomeprazole versus other proton pump inhibitors in erosive esophagitis: a meta-analysis of randomized clinical trials. Clin Gastroenterol Hepatol. 2006;4:1452-1458.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 121]  [Cited by in F6Publishing: 128]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
36.  Hirano I, Richter JE. ACG practice guidelines: esophageal reflux testing. Am J Gastroenterol. 2007;102:668-685.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 269]  [Cited by in F6Publishing: 248]  [Article Influence: 15.5]  [Reference Citation Analysis (0)]
37.  Sifrim D, Castell D, Dent J, Kahrilas PJ. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut. 2004;53:1024-1031.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 600]  [Cited by in F6Publishing: 628]  [Article Influence: 33.1]  [Reference Citation Analysis (0)]
38.  Cool M, Poelmans J, Feenstra L, Tack J. Characteristics and clinical relevance of proximal esophageal pH monitoring. Am J Gastroenterol. 2004;99:2317-2323.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 37]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
39.  Smith J, Woodcock A, Houghton L. New developments in reflux-associated cough. Lung. 2010;188 Suppl 1:S81-S86.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 24]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
40.  Abou-Ismail A, Vaezi MF. Evaluation of patients with suspected laryngopharyngeal reflux: a practical approach. Curr Gastroenterol Rep. 2011;13:213-218.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 24]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
41.  Wiener GJ, Richter JE, Copper JB, Wu WC, Castell DO. The symptom index: a clinically important parameter of ambulatory 24-hour esophageal pH monitoring. Am J Gastroenterol. 1988;83:358-361.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Weusten BL, Roelofs JM, Akkermans LM, Van Berge-Henegouwen GP, Smout AJ. The symptom-association probability: an improved method for symptom analysis of 24-hour esophageal pH data. Gastroenterology. 1994;107:1741-1745.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Harding SM. Recent clinical investigations examining the association of asthma and gastroesophageal reflux. Am J Med. 2003;115 Suppl 3A:39S-44S.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 56]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
44.  Harding SM. Pulmonary complications of gastroesophageal reflux. In: The Esophagus[M]. 4th ed. Philadelphia: Lippincott Williams and Wilkins 2004; 530-545.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Field SK, Sutherland LR. Does medical antireflux therapy improve asthma in asthmatics with gastroesophageal reflux?: a critical review of the literature. Chest. 1998;114:275-283.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 156]  [Cited by in F6Publishing: 166]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
46.  Saber H, Ghanei M. Extra-esophageal manifestations of gastroesophageal reflux disease: controversies between epidemiology and clicnic. Open Respir Med J. 2012;6:121-126.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 13]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
47.  Field SK, Gelfand GA, McFadden SD. The effects of antireflux surgery on asthmatics with gastroesophageal reflux. Chest. 1999;116:766-774.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 81]  [Cited by in F6Publishing: 84]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
48.  Coughlan JL, Gibson PG, Henry RL. Medical treatment for reflux oesophagitis does not consistently improve asthma control: a systematic review. Thorax. 2001;56:198-204.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 49]  [Cited by in F6Publishing: 54]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
49.  Pacheco-Galván A, Hart SP, Morice AH. Relationship between gastro-oesophageal reflux and airway diseases: the airway reflux paradigm. Arch Bronconeumol. 2011;47:195-203.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 26]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
50.  Komatsu Y, Hoppo T, Jobe BA. Proximal reflux as a cause of adult-onset asthma: the case for hypopharyngeal impedance testing to improve the sensitivity of diagnosis. JAMA Surg. 2013;148:50-58.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 36]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
51.  Irwin RS, Madison JM. Anatomical diagnostic protocol in evaluating chronic cough with specific reference to gastroesophageal reflux disease. Am J Med. 2000;108 Suppl 4a:126S-130S.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 47]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
52.  D’Urzo A, Jugovic P. Chronic cough. Three most common causes. Can Fam Physician. 2002;48:1311-1316.  [PubMed]  [DOI]  [Cited in This Article: ]
53.  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;94:3131-3138.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 172]  [Cited by in F6Publishing: 185]  [Article Influence: 7.7]  [Reference Citation Analysis (0)]
54.  Kiljander TO, Salomaa ER, Hietanen EK, Terho EO. Chronic cough and gastro-oesophageal reflux: a double-blind placebo-controlled study with omeprazole. Eur Respir J. 2000;16:633-638.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 99]  [Cited by in F6Publishing: 109]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
55.  Hanson DG, Kamel PL, Kahrilas PJ. Outcomes of antireflux therapy for the treatment of chronic laryngitis. Ann Otol Rhinol Laryngol. 1995;104:550-555.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 146]  [Cited by in F6Publishing: 148]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
56.  Noordzij JP, Khidr A, Evans BA, Desper E, Mittal RK, Reibel JF, Levine PA. Evaluation of omeprazole in the treatment of reflux laryngitis: a prospective, placebo-controlled, randomized, double-blind study. Laryngoscope. 2001;111:2147-2151.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 162]  [Cited by in F6Publishing: 166]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
57.  Smit CF, van Leeuwen JA, Mathus-Vliegen LM, Devriese PP, Semin A, Tan J, Schouwenburg PF. Gastropharyngeal and gastroesophageal reflux in globus and hoarseness. Arch Otolaryngol Head Neck Surg. 2000;126:827-830.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 46]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
58.  Delahunty JE. Acid laryngitis. J Laryngol Otol. 1972;86:335-342.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 66]  [Cited by in F6Publishing: 65]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
59.  Ylitalo R, Ramel S. Extraesophageal reflux in patients with contact granuloma: a prospective controlled study. Ann Otol Rhinol Laryngol. 2002;111:441-446.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 59]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
60.  Jindal JR, Milbrath MM, Shaker R, Hogan WJ, Toohill RJ. Gastroesophageal reflux disease as a likely cause of “idiopathic” subglottic stenosis. Ann Otol Rhinol Laryngol. 1994;103:186-191.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 87]  [Cited by in F6Publishing: 88]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
61.  El-Serag HB, Lee P, Buchner A, Inadomi JM, Gavin M, McCarthy DM. Lansoprazole treatment of patients with chronic idiopathic laryngitis: a placebo-controlled trial. Am J Gastroenterol. 2001;96:979-983.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 166]  [Cited by in F6Publishing: 171]  [Article Influence: 7.8]  [Reference Citation Analysis (0)]
62.  Eherer AJ, Habermann W, Hammer HF, Kiesler K, Friedrich G, Krejs GJ. Effect of pantoprazole on the course of reflux-associated laryngitis: a placebo-controlled double-blind crossover study. Scand J Gastroenterol. 2003;38:462-467.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 110]  [Cited by in F6Publishing: 113]  [Article Influence: 5.7]  [Reference Citation Analysis (0)]
63.  Bortolotti M. Laryngospasm and reflex central apnoea caused by aspiration of refluxed gastric content in adults. Gut. 1989;30:233-238.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 41]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
64.  Loehrl TA, Smith TL. Chronic sinusitis and gastroesophageal reflux: are they related? Curr Opin Otolaryngol Head Neck Surg. 2004;12:18-20.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 26]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
65.  Loughlin CJ, Koufman JA. Paroxysmal laryngospasm secondary to gastroesophageal reflux. Laryngoscope. 1996;106:1502-1505.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 84]  [Cited by in F6Publishing: 87]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
66.  Maceri DR, Zim S. Laryngospasm: an atypical manifestation of severe gastroesophageal reflux disease (GERD). Laryngoscope. 2001;111:1976-1979.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 40]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
67.  Morrison M, Rammage L, Emami AJ. The irritable larynx syndrome. J Voice. 1999;13:447-455.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 166]  [Cited by in F6Publishing: 177]  [Article Influence: 7.4]  [Reference Citation Analysis (0)]
68.  Aydın E, Taştan E, ydoǧan F, Arslan N, Karaca G. Role of nasopharyngeal reflux in the etiology of otitis media with effusion. J Otolaryngol Head Neck Surg. 2011;40:499-503.  [PubMed]  [DOI]  [Cited in This Article: ]
69.  Sone M, Katayama N, Kato T, Izawa K, Wada M, Hamajima N, Nakashima T. Prevalence of laryngopharyngeal reflux symptoms: comparison between health checkup examinees and patients with otitis media. Otolaryngol Head Neck Surg. 2012;146:562-566.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 23]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
70.  Al-Saab F, Manoukian JJ, Al-Sabah B, Almot S, Nguyen LH, Tewfik TL, Daniel SJ, Schloss MD, Hamid QA. Linking laryngopharyngeal reflux to otitis media with effusion: pepsinogen study of adenoid tissue and middle ear fluid. J Otolaryngol Head Neck Surg. 2008;37:565-571.  [PubMed]  [DOI]  [Cited in This Article: ]
71.  Nissen R. [A simple operation for control of reflux esophagitis]. Schweiz Med Wochenschr. 1956;86:590-592.  [PubMed]  [DOI]  [Cited in This Article: ]
72.  DeMeester TR, Bonavina L, Albertucci M. Nissen fundoplication for gastroesophageal reflux disease. Evaluation of primary repair in 100 consecutive patients. Ann Surg. 1986;204:9-20.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 605]  [Cited by in F6Publishing: 631]  [Article Influence: 17.1]  [Reference Citation Analysis (0)]
73.  Toupet A. Technique d’oesophago-gastroplastie avec phrenogastropexie appliqué dans la cure radicale des hernies hiatales et comme complement de l’operation d’heller dans le cardiospasmes. Mem Acad Chir. 1963;89:394-399.  [PubMed]  [DOI]  [Cited in This Article: ]
74.  Lind JF, Burns CM, MacDougal JT. “Physiological” repair of hiatus hernia – manometric study. Arch Surg. 1965;91:233-237.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 82]  [Cited by in F6Publishing: 81]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
75.  Dor J, Humbert P, Paoli JM, Miorclerc M, Aubert J. [Treatment of reflux by the so-called modified Heller-Nissen technic]. Presse Med. 1967;75:2563-2565.  [PubMed]  [DOI]  [Cited in This Article: ]
76.  Hill LD. An effective operation for hiatal hernia: an eight year appraisal. Ann Surg. 1967;166:681-692.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 253]  [Cited by in F6Publishing: 259]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
77.  Belsey R. Mark IV repair of hiatal hernia by the transthoracic approach. World J Surg. 1977;1:475-481.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 37]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
78.  Rossetti M, Hell K. Fundoplication for the treatment of gastroesophageal reflux in hiatal hernia. World J Surg. 1977;1:439-443.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 144]  [Cited by in F6Publishing: 145]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
79.  Guarner V, Martinez N, Gaviño JF. Ten year evaluation of posterior fundoplasty in the treatment of gastroesophageal reflux: long-term and comparative study of 135 patients. Am J Surg. 1980;139:200-203.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 20]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
80.  Watson A, Spychal RT, Brown MG, Peck N, Callander N. Laparoscopic ‘physiological’ antireflux procedure: preliminary results of a prospective symptomatic and objective study. Br J Surg. 1995;82:651-656.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 46]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
81.  Dallemagne B, Weerts JM, Jehaes C, Markiewicz S, Lombard R. Laparoscopic Nissen fundoplication: preliminary report. Surg Laparosc Endosc. 1991;1:138-143.  [PubMed]  [DOI]  [Cited in This Article: ]
82.  Dallemagne B, Weerts J, Markiewicz S, Dewandre JM, Wahlen C, Monami B, Jehaes C. Clinical results of laparoscopic fundoplication at ten years after surgery. Surg Endosc. 2006;20:159-165.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 256]  [Cited by in F6Publishing: 205]  [Article Influence: 11.4]  [Reference Citation Analysis (0)]
83.  Meneghetti AT, Tedesco P, Galvani C, Gorodner MV, Patti MG. Outcomes after laparoscopic Nissen fundoplication are not influenced by the pattern of reflux. Dis Esophagus. 2008;21:165-169.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 16]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
84.  Tedesco P, Lobo E, Fisichella PM, Way LW, Patti MG. Laparoscopic fundoplication in elderly patients with gastroesophageal reflux disease. Arch Surg. 2006;141:289-292; discussion 292.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 44]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
85.  Patti MG, Robinson T, Galvani C, Gorodner MV, Fisichella PM, Way LW. Total fundoplication is superior to partial fundoplication even when esophageal peristalsis is weak. J Am Coll Surg. 2004;198:863-869; discussion 863-869.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 108]  [Cited by in F6Publishing: 88]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
86.  Society of American Gastrointestinal Endoscopic Surgeons (SAGES). Guidelines for Surgical Treatment of Gastroesophageal Reflux Disease (GERD).  Available from: http: //  [PubMed]  [DOI]  [Cited in This Article: ]
87.  Patti MG, Arcerito M, Feo CV, De Pinto M, Tong J, Gantert W, Tyrrell D, Way LW. An analysis of operations for gastroesophageal reflux disease: identifying the important technical elements. Arch Surg. 1998;133:600-606; discussion 600-606.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 61]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
88.  Herbella FA, Tedesco P, Nipomnick I, Fisichella PM, Patti MG. Effect of partial and total laparoscopic fundoplication on esophageal body motility. Surg Endosc. 2007;21:285-288.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 41]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
89.  Spechler SJ, Lee E, Ahnen D, Goyal RK, Hirano I, Ramirez F, Raufman JP, Sampliner R, Schnell T, Sontag S. Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial. JAMA. 2001;285:2331-2338.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 660]  [Cited by in F6Publishing: 691]  [Article Influence: 31.4]  [Reference Citation Analysis (0)]
90.  Ramos RF, Lustosa SA, Almeida CA, Silva CP, Matos D. Surgical treatment of gastroesophageal reflux disease: total or partial fundoplication? systematic review and meta-analysis. Arq Gastroenterol. 2011;48:252-260.  [PubMed]  [DOI]  [Cited in This Article: ]
91.  Wileman SM, McCann S, Grant AM, Krukowski ZH, Bruce J. Medical versus surgical management for gastro-oesophageal reflux disease (GORD) in adults. Cochrane Database Syst Rev. 2010;CD003243.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 78]  [Article Influence: 6.0]  [Reference Citation Analysis (0)]
92.  Sontag S, O’Connell S, Greenlee H, Schnell T, Chintam R, Nemchausky B, Chejfec G, Van Drunen M, Wanner J. Is gastroesophageal reflux a factor in some asthmatics? Am J Gastroenterol. 1987;82:119-126.  [PubMed]  [DOI]  [Cited in This Article: ]
93.  Pellegrini CA, DeMeester TR, Johnson LF, Skinner DB. Gastroesophageal reflux and pulmonary aspiration: incidence, functional abnormality, and results of surgical therapy. Surgery. 1979;86:110-119.  [PubMed]  [DOI]  [Cited in This Article: ]
94.  Hunter JG, Trus TL, Branum GD, Waring JP, Wood WC. A physiologic approach to laparoscopic fundoplication for gastroesophageal reflux disease. Ann Surg. 1996;223:673-685; discussion 685-687.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 293]  [Cited by in F6Publishing: 328]  [Article Influence: 12.1]  [Reference Citation Analysis (0)]
95.  Spechler SJ, Gordon DW, Cohen J, Williford WO, Krol W. The effects of antireflux therapy on pulmonary function in patients with severe gastroesophageal reflux disease. Department of Veterans Affairs Gastroesophageal Reflux Disease Study Group. Am J Gastroenterol. 1995;90:915-918.  [PubMed]  [DOI]  [Cited in This Article: ]
96.  Larrain A, Carrasco E, Galleguillos F, Sepulveda R, Pope CE. Medical and surgical treatment of nonallergic asthma associated with gastroesophageal reflux. Chest. 1991;99:1330-1335.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 177]  [Cited by in F6Publishing: 178]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
97.  Oelschlager BK, Quiroga E, Parra JD, Cahill M, Polissar N, Pellegrini CA. Long-term outcomes after laparoscopic antireflux surgery. Am J Gastroenterol. 2008;103:280-287; quiz 288.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 85]  [Cited by in F6Publishing: 80]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
98.  Swoger J, Ponsky J, Hicks DM, Richter JE, Abelson TI, Milstein C, Qadeer MA, Vaezi MF. Surgical fundoplication in laryngopharyngeal reflux unresponsive to aggressive acid suppression: a controlled study. Clin Gastroenterol Hepatol. 2006;4:433-441.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 104]  [Cited by in F6Publishing: 105]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]