Ghisa M., Coletta M.D., Barbuscio Il., et al. Updates in the field of nonesophageal gastroesophageal reflux disorder // Expert Review of Gastroenterology & Hepatology, 22 Jul 2019.

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Авторы: Ghisa M. / Coletta M.D. / Barbuscio I. / Marabotto E. / Barberio B. / Frazzoni M. / de Bortoli N. / Zentilin P. / Tolone S. / Ottonello A. / Lorenzon G. / Savarino V. / Savarino E.V.

Updates in the field of nonesophageal gastroesophageal reflux disorder

Matteo Ghisaa, Marco Della Colettaa, Ilenia Barbuscioa, Elisa Marabottob, Brigida Barberioa, Marzio Frazzonic, Nicola De Bortolid, Patrizia Zentilinb, Salvatore Tolonee, Andrea Ottonellof, Greta Lorenzona, Vincenzo Savarinob and Edoardo Savarinoa

a Gastrointestinal Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy;
b Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy;
c Baggiovara Hospital, Modena, Italy;
d Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy;
e Surgery Unit, Department of Surgery, University of Campania Luigi Vanvitelli, Caserta, Italy;
f Department of Surgical Science and Integrated Diagnostics, University of Genoa, Genoa, Italy

To cite this article: Matteo Ghisa, Marco Della Coletta, Ilenia Barbuscio, Elisa Marabotto, Brigida Barberio, Marzio Frazzoni, Nicola De Bortoli, Patrizia Zentilin, Salvatore Tolone, Andrea Ottonello, Greta Lorenzon, Vincenzo Savarino & Edoardo Savarino (2019) Updates in the field of non-esophageal gastroesophageal reflux disorder, Expert Review of Gastroenterology & Hepatology, DOI: 10.1080/17474124.2019.1645593

CONTACT. Edoardo Savarino edoardo.savarino@ Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Via Giustiniani 2, 351258 Padova, Italy

Аннотация на русском языке


Introduction: Gastroesophageal reflux disease (GERD) is one of the most prevalent conditions in Western Countries, normally presenting with heartburn and regurgitation. Extra-esophageal (EE) GERD manifestations, such as asthma, laryngitis, chronic cough and dental erosion, represent the most challenging aspects from diagnostic and therapeutic points of view because of their multifactorial pathogenesis and low response to proton pump inhibitors (PPIs). In fact, in the case of EE, other causes must by preventively excluded, but instrumental methods, such as upper gastrointestinal endoscopy and laryngoscopy, have low specificity and sensitivity as diagnostic tools. In the absence of alarm signs and symptoms, empirical therapy with a double-dose of PPIs is recommended as a first diagnostic approach. Subsequently, impedance-pH monitoring could help to define whether the symptoms are GERD-related.

Areas covered: This article reviews the current literature regarding established and proposed EE-GERD, reporting on all available options for its correct diagnosis and therapeutic management.

Expert opinion: MII-pH could help to identify a hidden GERD that causes EE. Unfortunately, standard MII-pH analysis results are often unable to define this association. New parameters such as the mean nocturnal baseline impedance and post-reflux swallow-induced peristaltic wave index may have an improved diagnostic yield, but prospective studies using impedance-pH are needed.

KEYWORDS. Extra-esophageal reflux syndrome; Laryngopharyngeal reflux; chronic cough; GERD; asthma; dental erosion; sinusitis; pulmonary fibrosis; otitis

Article highlights

● EE-GERD has a multifactorial pathogenesis and the part exclusively due to GER is certainly overestimated; other causes of EE symptoms must be excluded before suspecting GERD.
● Endoscopic signs of GERD by laryngoscopy are also present in healthy volunteers and are not specific to GERD diagnosis.
● Empirical double-dose PPI therapy is suggested by most guidelines, followed by a MII-pH study in patients who do not respond to PPIs.
● PPI therapy in EE-GERD usually has poor efficacy or no efficacy at all, especially in the absence of typical symptoms.
● Novel impedance parameters, including PSPW and MNBI, can enhance the usefulness of MII-pH in EE-GERD patients.
● When considering fundoplication, physicians must remember that only patients that respond to PPIs or those who have well-defined anatomical defects (e.g., hiatal hernia) are likely to show a good response to surgical treatment.

1. Introduction

Based on the 2006 Montreal definition, gastroesophageal reflux disease (GERD) is a condition that develops when the reflux of the stomach contents causes troublesome symptoms and/or complications (Figure 1) [1]. Typical manifestations of GERD are heartburn and regurgitation, which are defined as ‘esophageal syndrome’ or ‘typical GERD’ [1]. These symptoms are reported from Ancient Greek medicine, but pulmonary and laryngeal involvement in GERD were only first described from the early 1900s. Osler proposed the association between asthma and GERD, suggesting that respiratory attacks may be indirectly due to the reflux of contents from the stomach. Since the end of ‘80s, an increasing number of articles have shown that, besides classic manifestations, several patients complained of ‘atypical symptoms’ (extraesophageal GERD, EE-GERD) including chronic cough, hoarseness due to laryngitis, asthma attacks and dental erosion [1]. Moreover, in recent years, it has been supposed that many other conditions could be linked to GERD, but evidence is still lacking (Table 1).

2. Epidemiology

The prevalence of GERD has increased progressively over the last few decades [2], and many studies have reported a higher occurrence of this disease in Western Europe and North and South America, with rates between 10%-20%of the general population, even though a prevalence up to 40% has been described [3–9]. Globally, these rates are only lower than 10% in East Asia [3].

Regarding the prevalence of EE-GERD, the ProGERD study, which evaluated a large cohort of over 6,000 patients with heartburn, found that EE symptoms can be detected in 32.8% of all patients. The proportion was significantly higher in patients with erosive reflux disease (ERD) (34.9%) than in patients with non-erosive reflux disease (NERD) (30.5%) [10]. This study considered patients with concomitant heartburn and missed those with only EE symptoms; therefore, EE-GERD could have been more prevalent. Indeed, epidemiological research only considered patients with both typical and extra-esophageal symptoms, thus excluding those having EE-GERD alone. Therefore, the prevalence of EE-GERD is probably greater than what has been reported to date, and there are several studies in the literature, including a meta-analysis that evaluated laryngo-pharyngeal reflux in the general population, reporting an average rate of 30% [11,12].

Considering the large proportion of the population affected by GERD, public health costs are high, and in 2013, Francis et al. showed that expenses for the management of EE-GERD are considerably higher than those for GERD with esophageal symptoms and are comparable to those spent for cancer in the USA (Figure 2) [13].

3. Pathogenesis

GERD arises due to an imbalance between triggering and defensive factors (reflux events, reflux acidity, esophageal hypersensitivity versus esophageal reflux clearance, mucosal integrity, and mucosal resistance) [14]. The following are the three main pathophysiological mechanisms that determine the impairment of gastroesophageal junction (EGJ):

(1) Transient lower esophageal sphincter relaxation (TLESR). This is part of the physiological mechanism of eructation, consisting of an active, vagus-mediated reflex, which has the task of removing air from the stomach. The diagnosis is made by high resolution manometry (HRM) that shows a deep relaxation of the tone at the level of EGJ > 10 seconds without being accompanied by deglutition [15]. One of the main causes of GERD is the increase in TLESRs in terms of both duration and number associated with acid reflux [16]. Distension of the stomach fundus and upright position show an increased number of TLESRs.

(2) Hypotensive lower esophageal sphincter. This is a defect that affects a small proportion of GERD patients, occurring when the LES pressure value is less than 10 mmHg [17]. Factors that can reduce LES pressure include gastric distension, cholecystokinin, smoking, specific foods and drugs [18,19].

(3) Anatomical disruption of the EGJ. This is often associated with hiatal hernia, mainly due to the lack of anatomical superimposition between LES and the crural diaphragm [20–22].

These mechanisms can favor the proximal extension of reflux and the direct contact of gastric contents with the mucosa of several anatomical structures such as the rhino-pharynx, oral cavity, larynx and bronchial tree. However, evidence is conflicting [23]. Recently, Sakin et al. highlighted that patients with EE symptoms present a lower proximal baseline impedance, which is a marker of impaired esophageal mucosal integrity, compared with patients with typical esophageal symptoms (1997 ± 51 vs 2245 ± 109, p < 0.05) [24]. Similarly, Ribolsi et al. observed lower proximal baseline impedance values in patients with chronic cough responding to acid suppressive therapy (therefore with evidence of reflux-related cough) compared with those not responding to the same treatment (p < 0.01) [25].

A further aspect is the stimulation of sensitive neuro-receptors that are present in the  esophagealmucosa. The bronchial tree and esophagus have the same embryogenic origin and innervation. The passage of the esophageal bolus activates a reflex arc, promoting the sensitization of pharyngeal epithelial afferent pathways and constricting fibers that innervate the bronchi. This could explain how reflux that does not reach the proximal esophagus could result in EE symptoms [23]. This mechanism has been summarized in the double pathophysiological theory – the reflux/reflex theory [8].
4. Estabilished extraesophageal manifestation of GERD
4.1. Reflux-related laryngitis

Typically, patients with laryngitis are referred to an otolaryngologist, who takes compatible reflux pictures by laryngoscopy and should send them to the gastroenterologist. ‘Laryngopharyngeal reflux’ (LPR), and consequently reflux-related laryngitis, are welldefined clinical pathologies recognized by the Montreal classification as EE-GERD [1]. Although LPR is frequent, reflux is not the only cause of laryngitis. In fact, it can also be observed in patients with post-nasal drip (PND) and environmental exposure to allergens or other irritants, such as smoke. Reflux causes irritation and/or mucosal inflammation through direct contact or neuromediated reflex. A long series of symptoms are included under LPR, such as hoarseness, throat clearing, sore or burning throat, cough, pain with swallowing, oro-pharyngeal heartburn, voice fatigue, excessive phlegm and globus. GERD may also be responsible for laryngeal pathologies such as ulcerations, subglottic stenosis, vocal cord polyps, erythema and edema of the posterior larynx, granuloma, or even leucoplakia and cancer [8]. However, most signs are not specific for GERD, often leading to an overdiagnosis of reflux laryngitis [26]. Thus, in the first instance, other causes of laryngitis should be excluded. Based on available scientific data, only 40% of patients showing symptoms of laryngeal dysfunction have acid reflux by MII-pH, and this greatly reduces the specificity of chronic posterior laryngitis observed by laryngoscopy [27]. Weakly acidic and biliary reflux also play a role in promoting symptoms, especially in cases that do not respond to PPI therapy. Twenty-four hour MII-pH, which is able to detect both weakly acidic and weakly alkaline reflux in addition to acid reflux detectable with traditional esophageal pH-metry, is remunerative in these cases [28–34].

From a therapeutic point of view, several randomized controlled trials (RCTs) have been published during the last two years. A meta-analysis carried out by Chunhui Wei in 2016, including 13 RCTs on patients with LPR treated with PPIs, showed that twice-daily treatment with these drugs for 3–6 months could significantly improve reflux symptoms (standardized mean differences = 3.65; 95% CI 1.56–5.75) [35]. In contrast, differences in the response rate and effects on the laryngeal mucosa between PPIs and the placebo were not observed in other studies [36]. In a meta-analysis study from 2014, Ren et al. evaluated whether the combination of PPIs and prokinetics could be effective [37]. They analyzed 12 RCTs including 2403 patients and showed that the above combined therapy may partially improve patients’ quality of life (greater symptom score change; 95% CI: 2.14–3.02, P < 0.00001), but has no significant effect on the symptoms or endoscopic responses of EE-GERD [37]. These authors also recommended the adoption of lifestyle modifications, which can improve the symptoms associated with chronic pharyngo-laryngitis.

As to the causal relationship between GERD and laryngeal cancer, some studies have shown that LPR plays a role in this disease process [38], but data are still scant and more investigations are required to strengthen this relationship.

4.2. Reflux-related cough

Chronic cough is defined as the persistence of this symptom for more than 8 weeks and is one of the most common reasons for outpatient visits. Even if PND syndrome is thought to be one of the major causes of unexplained chronic cough, epidemiological data describe an association of this symptom with GERD in up to 21–41% of cases [39,40]. The following three mechanisms have been hypothesized for the induction of cough in GERD patients: (1) the microaspiration of gastric contents, (2) the proximal extension of reflux into the pharynx and larynx, and (3) the activation of a vagal esophagealbronchial reflex [41,42]. However, Smith et al. have questioned the first two mechanisms. With respect to microaspiration, a higher level of pepsin and/or bile acid in sputum or bronchoalveolar lavage fluid (BALF) was not found in patients with chronic cough compared to controls. Furthermore, it is still difficult to assess with precision the extension of reflux into the pharynx and larynx since current methods and investigational devices are poorly accurate [42,43]. Additionally, Smith et al. speculated that GERD could not only cause cough, but that cough may also cause reflux by increasing TLESRs [44].

As to a therapeutic approach, the AGA guidelines suggest administering a 12-week double-dose of PPI therapy before performing 24-h MII-pH to confirm GERD. Furthermore, before starting therapy, it is mandatory to exclude ear, nose and throat (ENT) disease [45]. The absence of esophageal symptoms in up to 64% of patients with presumed reflux cough seems to demonstrate that weakly acidic or non-acid reflux may also trigger cough, and this suggests that acid exposure is not the only determinant of symptom appearance. Interestingly, some data reveal a better clinical response in PND patients treated with PPIs compared to placebo groups [40,46–48]. Kahrilas et al. analyzed nine placebo-controlled randomized clinical trials and only two of them revealed a statistically significant reduction in cough frequency and/or severity after pharmacologic acid-suppressive therapy, although the efficacy was higher than the placebo [49]. Thus, the use of PPIs has not been recommended in the absence of typical GERD symptoms [50]. In fact, the therapeutic gain is generally higher in patients with abnormal acid exposure than in patients with simple reflux-symptom associations, as supposed by Smith [44,49]. Interestingly, Herregods et al. recently investigated the optimal time window to calculate the symptom association probability (SAP) for cough during 24-hour impedance-pH testing and concluded that it was two minutes, without a significant increase in sensitivity from two to five minutes [51]. This further refinement of the use of reflux-symptom associations could be helpful for the future definition of this association. According to the above-mentioned guidelines, apart from medical therapy, surgical treatment was suggested only in patient cases with abnormal MII-pH who did not respond to maximal three-month medical therapy [50]. Before performing a laparoscopic fundoplication, however, it is mandatory to rule out an esophageal motility disorder. To the best of our knowledge, no randomized controlled trials on surgical treatment of reflux-related chronic cough are currently available [49]. In contrast, it has been shown in accurately selected groups of patients that when GERD is documented by 24-h MII-pH, surgical treatment is effective in 85% of cases [52].

4.3. Reflux-related asthma

Among respiratory tract diseases associated with GERD, there is also asthma. In up to 80% of asthma cases, GERD has been found by MII-pH and among them, up to 40%-60% may not exhibit typical esophageal symptoms [53,54]. A strong association between GERD and asthma has been observed, but causality is not completely clear. The double pathogenic theory of reflux-reflex is also valid for asthma [54]. Moreover, it must be stressed that drugs used for the treatment of asthma, such as beta 2 adrenergic receptor agonists or theophylline, could cause reflux due to their ability to promote smooth muscle relaxation, including in LES [55]. Due to its obstructive pattern, asthma can increase the negative intra-thoracic pressure, which can favor reflux through the LES [54]. As has already been described for chronic cough, it is also likely that asthma increases the severity of GERD [56]. Experiments on rats demonstrated the usefulness of IL-5 and inflammatory cell detection in BALF to discriminate GERD-related asthma from allergy [56]. The correlation between atopic disorders and GERD was investigated by Hait and McDonald, who confirmed it to be stronger for asthma compared with other conditions [57]. Given the well-known anti-inflammatory effect of PPIs, their empirical administration in asthmatic patients is suggested by the National Institute of Health (NIH) guidelines, as well as in the absence of reflux disease [58]. Sandur et al. confirmed the efficacy of omeprazole in patients with asthma and concomitant GERD in terms of improvements in both nocturnal and daytime symptoms [53]. However, there are also studies that do not confirm the efficacy of PPIs, showing that the placebo is also effective [59].

4.4. Reflux-related dental erosion

Dental erosion (DE) consists of the loss of hard tooth substances due to a chemical dissolution process that does not involve bacteria [60]. DE can be considered the predominant oral manifestation of GERD. In addition to GERD, rumination, chronic vomiting, bulimia, bruxism and soft drink consumption also represent etiological factors associated with this pathology.

A prevalence of 20%-45% can be estimated in the general population, and this increases with age. In symptomatic GERD patients, a DE prevalence of 17%–68% was reported, and GERD was found in 25%–83% of patients showing DE, many of whom were children [61,62]. In 2015, data obtained by MII-pH performed in patients referred to dentists for erosive teeth showed that despite a less than once a week symptom frequency (73%), abnormal reflux parameters were found in greater than 69% of patients. This suggested the possibility of silent reflux in the majority of patients with DE [61]. The above study also demonstrated no significant correlation between DE scores and quantitative reflux indicators (% of time with pH < 4 or < 5.5 and number of proximal reflux episodes). Among all causes of DE, only GERD and eating disorders are associated with vomiting, showing a significant increase in this alteration compared to what happens in the general population [63].

From a pathophysiological point of view, even though a reduction in tooth wear is physiological with age, repeated or prolonged exposure to gastric secretions (pH < 2 vs normal salivary pH between 6.5 and 7.4) may accelerate this process [61]. Initially, there is the loss of protective tooth pellicle, followed by demineralization of the enamel at a pH of 5.5 and below, with dissolution of hydroxyapatite crystals, and finally, structural matrix changes in the underlying dentine, with open dentinal tubules. Saliva, which contains bicarbonates, antimicrobial substances, calcium and phosphate, is the main protective mechanism that can stop demineralization and promote mineralization. DEs due to acid reflux usually affect the lingual or palatal surfaces of the anterior teeth, mainly in the maxillary arch, with severity ranging from only a mild loss of enamel to a severe exposure of dentin. This is followed by episodes of dentinal hypersensitivity to external insults, such as cold, air and hyperosmotic substances, including sugar.

From a therapeutic point of view, the first thing to do is the adoption of specific lifestyle measures, such as avoiding soft drink consumption and, given the relevance of night-time reflux episodes, elevating the head of the bed. Medical therapy is obviously the same as for typical GERD, i.e., PPIs, antacids and alginates, and eventually, surgery. In a recent prospective longitudinal study, it was observed that chronic therapy with esomeprazole (20 mg b.i.d. for 1 year) blocked the progression of erosions in most (74%) of the patients enrolled in the study [62]. The management of DE resulting from GERD should be multidisciplinary to quickly introduce preventive and therapeutic measures and optimize the therapeutic benefits.
5. Proposed extraesophageal manifestations of GERD
5.1. Oral soft tissue lesions

It has been assumed that the oral effects of gastric acid reflux were not only directed at hard tissues but also at soft tissues. GERD patients sometimes suffer from burning mouth sensations, tongue sensitivity and non-specific pharyngeal itching. Nevertheless, correlations with pathognomonic oral mucosal lesions were not mentioned or identified in the scientific literature, excluding a few studies [64]. Periodontal disease, which is the most common dental disease in adults, has not been studied in patients with reflux. An old study conducted on patients affected by anorexia nervosa and bulimia, whose gastric reflux promotes an oral pH reduction, has detected a higher incidence of gingivitis but no differences in periodontitis [65]. Vinesh et al. reported that the majority of GERD patients showed oral lesions, with diffuse dental erosions, followed by periodontitis (1 in 4 patients) and gingivitis (1 in 10 patients) [66]. In 2015, Deppe et al. did not show statistically significant differences between ERD and NERD patients regarding the prevalence of oral mucosal lesions. However, severe periodontitis is significantly more frequent in ERD patients compared to NERD patients (p < 0.001) [67]. Therefore, PPI use had no negative impact on the prevalence of acidic oral mucosal lesions and periodontal destruction

5.2. Halitosis

Halitosis is among oral changes related to GERD and represents a chronic condition of oral bad smell, causing personal discomfort and social embarrassment. It can have several origins ranging from oral to systemic conditions. Moskowitz et al. noted that GERD is strongly related to the occurrence and severity of halitosis based on data obtained with self-administered questionnaires [68]. In contrast, a study published by Lee et al. using information obtained from both questionnaires and a Halimeter, an instrument that measures volatile sulfur compounds (VSCs), did not find a significant relationship between GERD and halitosis [69]. Moreover, when comparing ERD and NERD populations, no differences were found with either test [70]. Therefore, a causal association between GERD and halitosis still remains controversial. More objective data collection, such as that obtained from the detection of products containing VSCs, is mandatory to achieve a more solid correlation between these two problems [60].

5.3. Chronic rhino-sinusitis

Chronic rhino-sinusitis (CRS) is a common condition characterized by inflammation and swelling of the cavities around the nasal passages (sinuses) for at least 12 weeks despite treatment attempts. GERD has been reported to occur in CRS more frequently than expected, though the correlation is still presumptive since strong evidence is lacking. Regarding the pathophysiological background, pepsin and acid pH could be involved. In fact, pepsin levels in nasal secretions from CRS patients are significantly higher compared to controls (p < 0.001), and in-vitro studies observed that pepsin promotes cellular necrosis from mitochondrial damage [71,72]. Even Helicobacter pylori infection could play a pathogenic role, considering its higher prevalence in the nasal and paranasal mucosa of patients affected by CRS compared to controls [73].

A prospective cohort study conducted on more than 15,000 Thai people reported a higher incidence of CRS in patients affected by GERD compared to the general population (relative risk of 2.36 times, p < 0.001) [74]. Nevertheless, epidemiological correlation between these two characteristics might be incidental or depend on common causal agents or triggers (such as smoking) or rely on other factors, such as NSAIDs used to treat painful sinusitis, which can in turn exacerbate GERD [75]. A recent prospective study based on a 10-year follow-up of more than 5,000 patients showed that patients suffering from nocturnal GERD at baseline had a higher 10-year risk of developing CRS compared to patients not affected by GERD (p < 0.001). Additionally, the number of episodes was proportional to the risk (p = 0.02) [76]. A study published in 2017 showed that patients affected by CRS had abnormal pH-MII in terms of the total number of refluxes and number of proximal refluxes compared to controls (p < 0.0005) [77]. Furthermore, patients with nasopharyngeal reflux have CRS that is persistent and poorly responsive to therapy, demonstrating that GERD could have a negative prognostic value in this condition [73].

With respect to the therapeutic aspects, few studies have evaluated the efficacy of PPIs on CRS symptoms and natural history. Di Baise et al. showed that a 3-month treatment with omeprazole b.i.d. only promoted a mild improvement of CRS symptoms, without reaching complete clinical remission [78]. Based on all the studies conducted so far, only a simple correlation and not causality has been documented between GERD and CRS. Hence, anti-reflux measures should be considered as an option when documented acid-reflux is present in CRS and other etiologies have been excluded. Nevertheless, more prospective RCTs are needed to provide evidence of sufficient quality.

5.4. Pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive respiratory disease of unknown origin that is limited to the lungs and affects adults. It is characterized by fibrotic changes in the pulmonary interstitium and leads to a progressive functional deficit, resulting in death [79]. From the pathological point of view, it seems that repeated insults trigger an excessive and redundant reparative process, promoting fibrosis of the lungs. Additionally, gastro-esophageal reflux (GER) appears to be one of these factors [79]. Several studies have shown that GERD is more common in patients with IPF than in the general population and is characterized by being clinically silent in a high percentage of cases [80,81]. For instance, Savarino et al. compared IPF patients with non-idiopathic pulmonary fibrosis subjects and healthy volunteers. IPF patients had significantly higher esophageal acid exposure and proximal reflux events compared to both control groups. Moreover, pulmonary fibrosis, as expressed by HRCT scores, significantly correlated with reflux episodes in both the distal and proximal esophagus. Finally, it was found that patients with IPF had more bile acids and pepsin in BALF (62% and 67%, respectively) and saliva (61% and 68%, respectively) than non-IPF patients (25% and 25% in BALF and 33% and 36% in saliva, respectively) and controls (0% and 0% in BALF and saliva, respectively) [82]. Microaspiration has also been studied in patients with systemic sclerosis, showing that it can similarly promote pulmonary fibrosis [83].

A pooled analysis of patients with IPF who were previously enrolled in three randomized controlled trials showed that the use of anti-GER drugs (in particular PPIs and histamine H2 receptor antagonists) slows the decline in the forced vital capacity (FVC) (p = 0.05) and the frequency of disease exacerbations (p < 0.01), but does not improve survival [84]. A recently published meta-analysis evaluated the relationship between GERD and IPF by analyzing 18 case-control studies. In the first assessment, the two pathologies seemed to be associated, but after meta-regression and controlling for smoking, GERD and IPF were not clearly related [85].

Although current guidelines recommend the use of antisecretory therapy to treat IPF, the literature lacks data that support this recommendation [86,87]. Moreover, there are studies that suggest that PPIs not only do not improve outcomes but also increase the risk of respiratory infections in these patients [79,88]. In summary, randomized controlled trials focused on antisecretory therapy in IPF are mandatory [89].

5.5. Recurrent otitis media

Otitis media with effusion (OME) is the presence of nonpurulent secretions within the middle ear. A correlation between OME and GERD has been proposed since the 2000s. Acid reflux can damage the mucous membrane of the ear directly and indirectly by promoting edema in the tube area, resulting in obstruction and impairment of the aeration of the middle ear. High levels of pepsin/pepsinogen (up to a 1000-fold greater than serum levels) in the middle ear effusions (MEEs) of children were first reported by Tasker in 2002 [90]. Fifteen years ago, Poelmans et al. first described that all patients with OME had evidence of GERD by EGD and MII-pH (esophagitis and/or abnormal reflux) [91]. They also observed that PPIs promoted the cessation of middle ear drainage and the chronic refractory feeling of pressure in the ear. In 2016, Górecka-Tuteja et al. showed that children affected by OME have GERD in 35.7% of cases, with most showing predominantly weakly acidic reflux episodes (87.8%) [92]. With respect to OME in adult populations, PPIs and conservative anti-reflux measures such as lifestyle modifications could be suggested. However, anti-reflux therapy for otitis media cannot be approved based on existing research, as there are only two randomized clinical trials regarding this topic, and neither had clear results [93]. In conclusion, although studies that contemplate the association between GERD and OME continue to multiply, there is a great number of articles in the literature that deny this relationship [94]. There is strong evidence supporting the relationship between GERD and OME in children. In contrast, this relationship is still doubtful in adults, demonstrating that more studies are necessary to realize whether this relationship is also applicable to adults.

5.6. Obstructive sleep apnea

The prevalence of symptomatic GERD in obstructive sleep apnea (OSA) ranges from 25% to 39%, which is higher than in the general population 95. The fact that these two pathologies have common risk factors, such as obesity and sleepiness, could justify the epidemiological association between them [95]. The relationship is bidirectional since sleep disturbances are risk factors for GERD, and vice versa [96]. Several studies have evaluated the effectiveness of PPIs for improving sleep quality as well as for other EE symptoms, though the outcomes are only good when OSA is associated with typical GERD symptoms. The characterization of GERD by MII-pH, particularly focused on evaluating nocturnal GER, is necessary, and in the case of positive results, trials with PPIs are mandatory [96].

6. Diagnostic options

There are currently no laboratory tests or instrumental investigations that allow us to make a safe and clear diagnosis of EE-GERD. A 3-month therapy with maximal PPI dosage b.i.d. is used to define whether the suspected symptoms are GERD-related. Non-response of EE symptoms to PPIs does not allow us to exclude GER as a causative factor given the presence of weakly acidic and biliary reflux. A recent study by Vaezi et al. reviewed all the instrumental techniques and pharmacological options at our disposal [23] (Figure 3). With regards to the instrumental investigations, EGD is frequently the first diagnostic step, but endoscopic detection of reflux lesions (esophagitis) is not enough to identify reflux as a cause of EE in pictures. Therefore, it must be considered that there is a high prevalence of lesions in patients not showing symptoms of GERD (up to 20% of healthy controls), as only a few patients with LPR have esophageal lesions. Additionally, patients undergoing EGD are often taking or have taken PPI therapy, and this can modify the endoscopic picture.

Another important diagnostic tool is laryngoscopy, which is considered by otolaryngologists as the best way to detect LPR. Unfortunately, laryngeal signs attributable to reflux can be found in up to 86% of healthy subjects and have a high level of both inter- and intra-observer variability [23]. For this reason, laryngoscopy-based diagnosis of EE-GERD is often wrong and overestimates the frequency of this etiology. A second diagnostic is represented by HRM with reflux monitoring. This method allows us to evaluate the tone of UES and LES, the anatomy of EGJ (e.g., hiatal hernia) and the presence of TLESRs. All this information, which is associated with clinical and anamnestic findings, can refine the correlation of GER with EE symptoms. MII-pH, which is better than pH-monitoring alone, is extremely useful for determining the proximal extent of refluxate within the esophagus and characterizing the chemical nature of the refluxate in acid as either a weakly acidic or weakly alkaline type [97,98]. A useful parameter is the total number of refluxes registered, and values < 40 refluxes/24 h are considered normal, while 80 refluxes/24 h are considered abnormal. Another useful parameter is the esophageal acid exposure time (AET), which is extracted from both pH and MII-pH measurements and refers to the percentage of time when the pH in the distal esophagus is < 4.0. This is the most reproducible parameter and correlates with the response to PPIs [99]. An abnormal AET in an upright position is usually due to altered EGJ function and is mostly due to increased TLESRs, which are mainly expressed during the daytime. A further important aspect is the proximal migration of the refluxate. As to the pathophysiological mechanisms of the direct contact of refluxate with the upper respiratory tract mucosa, the evaluation of all the above data could be useful to support a correlation between reflux and EE-GERD.

Another critical aspect is the temporal correlation of symptoms with GER and, accordingly, several symptom-correlation indexes, such as the symptom index score (SI) and the symptom association probability (SAP). SI is the ratio between the number of reflux-related symptomatic episodes and the total number of symptomatic episodes and therefore describes the percentage of symptoms related to reflux. The limitation of this parameter is that it does not consider the total number of reflux episodes. An SI greater than 50% represents a positive association, and most studies use a 5-minute time window to calculate the SI. SAP is a much more complex parameter and is calculated by dividing the 24-h MII-pH findings into consecutive 2-minute segments and considering in which segments symptoms and refluxes are present, either alone or together. A value of 95% represents a positive symptom association. Many studies have shown that SAP is much more reproducible than SI.

The above two traditional parameters predict the response to PPIs independently from the AET. However, if this is true for esophageal symptoms, it is doubtful for extra-esophageal symptoms. When considering dental erosion or laryngitis, the calculation of these scores is not possible. In the same way, the relationship between GERD and asthma attacks cannot be routinely evaluated via 24-h monitoring. For these symptoms, the etiological relationship must be evaluated in terms of chronic irritation/inflammation and exacerbation of symptoms, instead of a 1:1 correlation during pH monitoring. Most studies evaluating the SI and SAP in EE-GERD have been performed in patients with chronic cough and showed a good correlation between this symptom and reflux episodes. However, there are also important limitations for chronic cough because patients can often forget to report their symptoms during the 24-hour pH monitoring. However, acoustic detectors can bypass this problem and correctly assess all cough episodes. Altogether, while studies so far have produced some good evidence in patients with chronic cough, the inability of SAP and SI to correctly correlate symptoms with reflux episodes in other forms of EE-GERD is a challenge. Therefore, despite these scores, the diagnostic yield of MII-pH is significantly lower in extra-esophageal compared with esophageal symptoms.

Moreover, MII-pH analysis can be performed in patients ‘ON’ or ‘OFF’ PPIs presenting esophageal or extra-esophageal symptoms, but not responding to acid suppressive therapy. The Lyon Consensus stated that testing should be performed ‘OFF’ PPIs to demonstrate an altered AET, give a more reliable assessment of the patient’s picture, and eventually establish an indication for anti-reflux surgery. Performing MII-pH contextually to a maximal PPI dosage (‘ON’ PPI) is indicated in patients with known and documented reflux disease to evaluate the ability of medical therapy to control GER [99]. However, studies conducted on patients who do not respond to PPIs have shown that acid reflux is only present in a minority of patients (10%), while non-acidic reflux increases remarkably and is prevalent (40%) [23]. Other diagnostic options, such as the detection of pepsin in the saliva, are emerging, but while this test correlates well with typical symptoms [100], its performance is disappointing in the case of extra-esophageal symptoms [101].

7. Therapeutic options

Acid suppressive therapy has great importance and represents the general standard of care at the moment, though it is supported by poor scientific evidence. A 3-month therapy with maximal dosage PPI b.i.d. is the first therapeutic approach for EE symptoms in clinical practice. If there is a response to PPIs, the minimum effective dose must be maintained long-term. As mentioned above, non-response to PPIs does not allow us to exclude GER as a causative agent, especially considering the possibility of weakly acidic and biliary refluxes. There are many studies focused on LPR, laryngitis, asthma and chronic cough, but their results are inconsistent and only a few are RCTs. The main point is the need to characterize patients accurately since only a minority of them respond to antisecretory therapy, which is usually those with typical symptoms associated with EE-GERD. The absence of regurgitation generally suggests the exclusion of non-acid reflux and promotes the search for other etiologies, which should never be done. PPIs are the main drugs examined in the literature; however, they are not the only drugs that have been evaluated for EE-GERD. With respect to H2 blockers, studies on EE symptoms, predominantly on asthma, are limited, old (pre-PPIs) and have conflicting results. Similarly, there is no clear evidence for the effectiveness of prokinetics, although some studies have shown that their association with PPIs could improve LPR. It has also been observed that alginate has discrete results on chronic cough. Baclofen, thanks to its capacity to inhibit TLESRs, has been used alone or in association with PPIs and have been shown to be effective for chronic cough in both clinical trials and case series. A recent study has confirmed the general opinion that patients who exhibit esophageal symptoms in addition to important anatomical lesions have a better response to PPIs (99).

The last option available is surgical therapy by means of fundoplication, but before referring patients with EE-GERD for surgery, the risk-benefit ratio should be carefully considered. Studies focused on this topic are numerous but are prevalently observational, retrospective or case reports. Trials comparing surgery to PPIs do not exist yet. An old study compared the efficacy of fundoplication with H2RAs in patients with GERD and asthma and showed better results for surgery [102].

In conclusion, considering all the above-mentioned medications, there are only low-quality data suggesting the efficacy of their use for EE symptoms alone. However, an empirical trial of PPIs given b.i.d. should be considered after the exclusion of other etiologies, mostly when esophageal and EE symptoms are concomitant. Surgical therapy could be an effective option in patients responding to PPIs who cannot/will not continue to take these drugs chronically or who have an important anatomical defect (e.g., hiatal hernia). For other patients or when MII-pH is normal, surgery must be highly discouraged.

8. Expert opinion

The presence of typical symptoms allows us to perform a clinical diagnosis of GERD, though this is not possible when only extra-esophageal symptoms are present. Currently, many patients with typical symptoms are managed by primary care and usually respond to PPI therapy. Thus, the management of extra-esophageal symptoms has become the main challenge for gastroenterologists. Often, other specialists, particularly ENT doctors, tend to define patients as affected by GERD, particularly when another explanation for EE symptoms is not found. Thus, a there is a higher probability of overestimating GERD incidence in these patients. This is why modern international guidelines suggest to perform MII-pH in the absence of typical symptoms and in cases of symptoms refractory to PPIs to confirm the diagnosis and stop PPI therapy when the test is negative. We would like to stress that the absence of a response to PPIs is not sufficient to exclude GERD. Conventional parameters and normal values have been shown to have relevant limitations when diagnosing GERD; thus, the Lyon Consensus updated the diagnostic MII-pH criteria by pointing out attention to ‘the grey area’ between safely negative and positive MII-pH tests. Moreover, new parameters have been proposed to ameliorate the sensitivity and specificity of MII-pH for diagnosing GERD and clarifying PPI-refractory mechanisms. The mean nocturnal baseline impedance (MNBI) and post-reflux swallow-induced peristaltic wave index (PSPW) appear to be useful tools to diagnose GERD and improve the correlation with the therapeutic response to PPIs compared to conventional parameters such as acid exposure time [103–107]. The PSPW index evaluates the swallow-induced peristaltic wave occurring within 30 seconds from the end of reflux episodes, relating it with the number of total refluxes. It is able to separate patients with erosive vs non-erosive reflux disease and both from healthy subjects. In the same way, baseline impedance monitoring allows the evaluation of reflux-related impairment of the mucosal integrity, even if macroscopic mucosa patterns are normal. MNBI is the mean of three 10-minute night-time period evaluations selected without swallows or reflux episodes and reflects the nocturnal bedtime period. The current shortcomings of both of these parameters are that manual evaluation of MII-pH tracings and calculations are necessary. However, a careful manual review of MII-pH tracings is routinely suggested to elaborate conventional variables because automatic software analysis is hindered by a considerable error rate and does not guarantee accurate results. However, their calculation requires only a few minutes during manual tracing analysis.

Overall, these two new MII-pH variables, which are highly applicable and reproducible, appear to be able to improve the diagnostic yield for the identification of esophageal GERD-related symptoms. At the moment, unfortunately, data are lacking for translating these considerations to EE-symptoms.

A novel technique is represented by the measurement of the mucosal impedance (MI) during an endoscopic examination, which avoids the long duration and min-invasiveness of MII-pH testing. A study by Kavitt et al. (105) investigated MI in patients with EE symptoms in a prospective longitudinal cohort study and found that patients with EE symptoms and esophagitis have a distal MI less than those without esophagitis. These authors concluded that MI may be a useful and quicker tool to assess the presence of GERD in patients presenting EER symptoms.

To date, MII-pH remains the gold standard for the diagnosis of GERD, and specialists should not fear excluding the possibility of GERD-related EE symptoms in the case of negative MII-pH testing. Nevertheless, more prospective studies using MII-pH are needed to identify a clear relationship between GERD and EE symptoms. Moreover, when this is possible, the clinical relevance of some extra-esophageal GERD symptoms should be reconsidered.

In the near future, no significant changes are expected from a diagnostic and therapeutic point of view. Improvements in the management of these patients will result from the better use of MII-pH, which probably represents the greatest innovation in the field of GERD after the introduction of PPIs in 1988. New pH-MII scores, such as PSPW and MNBI, have the potential to identify the real pathogenic role of GER and to offer personalized approaches to patients.

From a therapeutic point of view, the majority of interventions are based on acid suppression with traditional powerful PPIs, and hopefully with new acid-lowering drugs such as vonoprazan. Although the body of literature is large, there are few well-designed RCTs aimed at comparing the currently available treatments and their effectiveness in patients with EE symptoms. It should be emphasized that while positive evidence of the association between EE and GERD symptoms and the efficacy of medical therapy is derived predominantly from case series, observational or retrospective studies, negative results mostly come from RCTs, and this contributed to reducing the past emphasis on the causal relationship between GERD and extra-esophageal symptoms.

However, emerging pathogenic evidence from the use of MII-pH testing shows that acid reflux is only one of the mechanisms involved. In fact, PSPW emphasizes the role of other mechanisms, such as altered peristalsis and chemical clearance of the esophageal mucosa, and MNBI indicates that the mucosal integrity is impaired in GERD patients. This novel information may be helpful for patients with EE-GERD and would therefore be necessary to broaden the therapeutic horizons by targeting other above-mentioned mechanisms to make our interventions effective in patients with both acid and non-acid-related symptoms.

Funding. This paper was not funded.

Declaration of interest. E. Savarino received lecture and Consultancy honoraria from Takeda, Janssen, MSD, Abbvie, Sofar, Malesci, Reckitt Benckiser, Medtronic. The authors have no other relevant affiliations or financial involvement with any organization
or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Vincenzo Savarino h ttp://
Edoardo Savarino h ttp://


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