**2. Clinical experience**

an immediate onset of effect within 1 h of administration, which is faster than a PPI and H2RA [31]. Compared with antacids, an alginate-based formulation is more effective than an antacid in controlling postprandial esophageal acid exposure and quickly relieving reflux symptoms, including heartburn, regurgitation, vomiting and belching, with longer duration [32–34]. Alginate-based formulations are also non-inferior to omeprazole in achieving a heartburn-free period in moderate episodic heartburn [35]. Therefore, alginate has the special properties of protection of the esophageal and upper respiratory mucosa from acid and nonacid reflux and displacement of acid pocket away from the esophagus, all of which make alginate an attractive agent in the management of refractory reflux symptoms with a cause other than by acid, such as NERD [36]. Compared with placebo, an alginate-antacid formulation demonstrated superior relief of reflux symptoms including heartburn and regurgitation in both patients with NERD and erosive esophagitis in a double-blind randomized controlled trial [37]. In another double-blind randomized clinical trial comparing the efficacy of alginate to omeprazole in patients with NERD, alginate demonstrated non-inferiority to omeprazole and was as effective as omeprazole for symptomatic relief [38]. Furthermore, adding alginate to a PPI can significantly relieve heartburn compared to using a PPI alone in patients with NERD, suggesting an additional benefit of alginate as add-on therapy in the management of

Interestingly, in a meta-analysis study, six of nine randomized trials found no difference between the PPI and placebo groups for LPR, whereas three trials exhibited statistically significant results [1]. In a systemic review, three of four randomized controlled studies revealed that prokinetic agents significantly reduced LPR symptoms, but there were too many study limitations to draw firm conclusions [40]. In a small randomized controlled study, a liquid alginate suspension could achieve significant improvement in the symptom scores and clini-

Therefore, on the basis of this discussed background, the management of suspected LPR is intriguing as it is very difficult, if even possible, to make a definitive diagnosis with the tools currently available [42]. If there is no doubt that many patients do have LPR symptoms, the probability of suspecting LPR, especially when typical reflux symptoms are lacking and PPIs do not improve symptoms, are low, mainly in non-specialist setting. LPR management is responsible of high economic burden mainly related to the prescription of PPIs, which may be, in most cases, not justified [3, 43, 44]. Therefore, in patients, initially visited by GP, who do not respond to a 2 to 3-month course of double dose PPI therapy, the role of the otolaryngologist is to document the presence of signs and symptoms suggestive of LPR with appropriate (i.e., validated and reproducible) investigations, namely fiber-endoscopy, and validated questionnaire (for example RSI and RFS). If LPR is documented, it is reasonable empirically testing these patients on PPIs to check for reflux control may be useful to select PPI-responder patients. If PPI are not adequate to control symptoms an add-on treatment should be prescribed. On the basis of the above-mentioned concepts, alginate could be a firstchoice option. As a matter of the fact, as there is no specific and focused medication able to irreversibly inactivate pepsin and block acid production, other compounds have place in LPR management, including medical devices with barrier effect. In the current scenario, an effective supportive strategy may be constituted by compounds able to strengthen the epithelial

refractory symptoms [39].

52 Esophageal Cancer and Beyond

cal findings of LPR [41].

As pointed out, the gastroesophageal reflux is considered a normal physiological process that usually happens after eating in healthy infants, children, young people and adults. In contrast, gastroesophageal reflux disease occurs when the effect of GER leads to symptoms severe enough to merit medical treatment. In clinical practice, it is difficult to differentiate between GER and GERD, and the terms are used interchangeably by health professionals and families alike. There is no simple, reliable and accurate diagnostic test to confirm whether the condition is GER or GERD, and this in turn affects research and clinical decisions [50–52]. Furthermore, the term GERD covers a number of specific conditions that have different effects and present in different ways. This makes it difficult to identify the person who genuinely has GERD, and to estimate the real prevalence and burden of the problem. Nevertheless, regardless of the definition used, GERD affects many subjects, who commonly seek advice from primary, secondary or tertiary care. As a result, it constitutes a major health burden for the Health Service. Moreover, if gastric refluxate moves more proximally into the laryngopharynx, it is defined laryngopharyngeal reflux (LPR). LPR should be considered as part of extraesophageal reflux (EER), reflux involving structures other than, or in addition to, the esophagus, and airway reflux involving proximal gastric reflux into the airways. LPR contributes to several otorhinolaryngologic symptoms and inflammatory disorders, and probably also to neoplastic diseases of the laryngopharynx, and seems to be also as common in children and infants as adults.

From a diagnostic point of view, GERD and LPR diagnosis may be performed on a clinical ground as there is no gold-standard diagnostic tool. In this regard, some questionnaires may very fruitful in clinical practice: Reflux Finding Score (RFS) based on signs viewed by laryngoscopy, Reflux Score Index (RSI) based on reflux symptoms, and GERD Impact Scale (GIS) based on frequency of symptoms, as reported in the tables (**Tables 1**–**3**).

From a management point of view, the guidelines suggest to give advice about GER and reassure patients and caregivers. Patients with dyspepsia with mild–moderate symptoms and without severe complications, such as bleeding, painful complaints, vomiting, could be treated with empirical full-dose PPI therapy for 4 weeks. Patients with GERD could be treated with a full-dose PPI for 4 or 8 weeks. If symptoms recur after initial treatment, a PPI could be offered at the lowest dose possible to control symptoms. In addition, it is recommended to encourage people who need long-term management of dyspepsia symptoms to reduce their use of prescribed medication stepwise: by using the effective lowest dose, by trying 'as-needed' use when appropriate, and by returning to self-treatment with antacid and/or alginate therapy (unless there is an underlying condition or co-medication that needs continuing treatment). It is also necessary to advise people that it may be appropriate for them to return to self-treatment with antacid and/or alginate therapy (either prescribed or purchased over-the-counter and taken as needed). Finally, it is important to avoid long-term, frequent dose and continuous antacid therapy (it only relieves symptoms in the short term rather than preventing them). On the basis of these considerations, proposed by guidelines, alginates may be considered as a valid and reasonable therapeutic option. A new medical device (Marial®), unique still now possessing the indication for both GERD and LPR, has been recently launched in the Italian market [53]. It is an innovative gel compound, containing magnesium alginate and E-Gastryal®. E-Gastryal® is a complex of phyto-polymers, keratin, Tara and Xantana gums, that are natural polysaccharides with high molecular weight and partially hydrosoluble, and able to provide viscosity to the solution and to generate a support frame where keratin peptide chains and hyaluronic acid anchor. Hyaluronic acid (HA) is a biopolymer with medium molecular weight characterized by optimal hygroscopic and hydrodynamic features. The chemical–physical properties of the polymeric complex confer mucoadhesiveness to E-Gastryal® so increasing the contact surface and the residence time on the mucous membranes of larynx, pharynx, and esophagus.

RSI > 13 = Abnormal Total

Abbreviation: RSI, reflux symptom index.

**Table 2.** Reflux Symptom Index.

**Within the last month, how did the following problems affect you? 0 = no problem**

1. Hoarseness or a problem with your voice 0 1 2 3 4 5 2. Clearing your throat 0 1 2 3 4 5 3. Excess throat mucus or postnasal drip 0 1 2 3 4 5 4. Difficulty swallowing food, liquids, or pills 0 1 2 3 4 5 5. Coughing after you ate or after lying down 0 1 2 3 4 5 6. Breathing difficulties or choking episodes 0 1 2 3 4 5 7. Troublesome or annoying cough 0 1 2 3 4 5 8. Sensation of something sticking in your throat or a lump in your throat 0 1 2 3 4 5 9. Heartburn, chest pain, indigestion, or stomach acid coming up 0 1 2 3 4 5

The Clinical Relevance of Gastroesophageal Reflux Disease and Laryngopharyngeal Reflux…

**5 = severe problem**

55

http://dx.doi.org/10.5772/intechopen.78357


In the past week

1. How often have you had the following symptoms


2. How often have you had difficulty in getting a good night's sleep because of your symptoms?

3. How often have your symptoms prevented you from eating or drinking any of the foods you like?

4. How often have your symptoms kept you from being fully productive in your job or daily activities?

5. How often do you take additional medication other than what the physician told you to take (such as Gaviscon, Maalox)?

**Table 1.** GERD Impact Scale (GIS).


**Table 2.** Reflux Symptom Index.

**None of the time 1**

between GER and GERD, and the terms are used interchangeably by health professionals and families alike. There is no simple, reliable and accurate diagnostic test to confirm whether the condition is GER or GERD, and this in turn affects research and clinical decisions [50–52]. Furthermore, the term GERD covers a number of specific conditions that have different effects and present in different ways. This makes it difficult to identify the person who genuinely has GERD, and to estimate the real prevalence and burden of the problem. Nevertheless, regardless of the definition used, GERD affects many subjects, who commonly seek advice from primary, secondary or tertiary care. As a result, it constitutes a major health burden for the Health Service. Moreover, if gastric refluxate moves more proximally into the laryngopharynx, it is defined laryngopharyngeal reflux (LPR). LPR should be considered as part of extraesophageal reflux (EER), reflux involving structures other than, or in addition to, the esophagus, and airway reflux involving proximal gastric reflux into the airways. LPR contributes to several otorhinolaryngologic symptoms and inflammatory disorders, and probably also to neoplastic diseases of the laryngopharynx, and seems to be also as common in children

From a diagnostic point of view, GERD and LPR diagnosis may be performed on a clinical ground as there is no gold-standard diagnostic tool. In this regard, some questionnaires may very fruitful in clinical practice: Reflux Finding Score (RFS) based on signs viewed by laryngoscopy, Reflux Score Index (RSI) based on reflux symptoms, and GERD Impact Scale (GIS)

based on frequency of symptoms, as reported in the tables (**Tables 1**–**3**).

In the past week

and infants as adults.

54 Esophageal Cancer and Beyond

reflux?

because of your symptoms?

drinking any of the foods you like?

**Table 1.** GERD Impact Scale (GIS).

productive in your job or daily activities?

1. How often have you had the following symptoms

**b.** Burning sensation in your chest or behind the breastbone?

**e.** Sore throat or hoarseness that is related to your heartburn or acid

2. How often have you had difficulty in getting a good night's sleep

3. How often have your symptoms prevented you from eating or

5. How often do you take additional medication other than what the

4. How often have your symptoms kept you from being fully

physician told you to take (such as Gaviscon, Maalox)?

**a.** Pain in chest/behind the breastbone?

**d.** Pain or burning in upper stomach?

**c.** Regurgitation or acid taste in your mouth?

**A little of the time 2**

**Some of the time 3**

**All of the time 4**

From a management point of view, the guidelines suggest to give advice about GER and reassure patients and caregivers. Patients with dyspepsia with mild–moderate symptoms and without severe complications, such as bleeding, painful complaints, vomiting, could be treated with empirical full-dose PPI therapy for 4 weeks. Patients with GERD could be treated with a full-dose PPI for 4 or 8 weeks. If symptoms recur after initial treatment, a PPI could be offered at the lowest dose possible to control symptoms. In addition, it is recommended to encourage people who need long-term management of dyspepsia symptoms to reduce their use of prescribed medication stepwise: by using the effective lowest dose, by trying 'as-needed' use when appropriate, and by returning to self-treatment with antacid and/or alginate therapy (unless there is an underlying condition or co-medication that needs continuing treatment). It is also necessary to advise people that it may be appropriate for them to return to self-treatment with antacid and/or alginate therapy (either prescribed or purchased over-the-counter and taken as needed). Finally, it is important to avoid long-term, frequent dose and continuous antacid therapy (it only relieves symptoms in the short term rather than preventing them).

On the basis of these considerations, proposed by guidelines, alginates may be considered as a valid and reasonable therapeutic option. A new medical device (Marial®), unique still now possessing the indication for both GERD and LPR, has been recently launched in the Italian market [53]. It is an innovative gel compound, containing magnesium alginate and E-Gastryal®. E-Gastryal® is a complex of phyto-polymers, keratin, Tara and Xantana gums, that are natural polysaccharides with high molecular weight and partially hydrosoluble, and able to provide viscosity to the solution and to generate a support frame where keratin peptide chains and hyaluronic acid anchor. Hyaluronic acid (HA) is a biopolymer with medium molecular weight characterized by optimal hygroscopic and hydrodynamic features. The chemical–physical properties of the polymeric complex confer mucoadhesiveness to E-Gastryal® so increasing the contact surface and the residence time on the mucous membranes of larynx, pharynx, and esophagus.


(64.6%) RELIEF patients had positive RSI score. RSI values for each single symptom are analytically reported in **Figure 1**. The symptoms with the highest score were: heartburning, sensation of something sticking in the throat or a lump in the throat, and clearing throat, whereas breathing difficulties or choking episodes had the lowest score. The total score was 16 [14–20] in the EMERGE patients was significantly higher than in the RELIEFE patients: 16 [12–20] (p < 0.001; data not shown). Interestingly, RELIEF patients had significantly higher scores for some symptoms, including lump sensation, cough, dyspnea, hoarseness, and throat clearing, whereas EMERGE patients had higher scores for heartburn and difficult swallowing. So, the clinical

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57

features were really different in the two populations, such as GERD and LPR patients.

Considering the previous treatments, the frequency of past/current treatments in the EMERGE group (**Figure 2A**) was significantly higher than in RELIEF group (**Figure 2B**) patients (p< 0.0001): this outcome underlines the more intense recourse to medical therapy in GERD patients than in LPR patients. Analyzing the treatment options, **Figure 3** shows the distribution of different types of treatments prescribed in the past (panel A, C) or currently used (panel B, D): monotherapy with PPI, PPI in add-on, and Miscellany in EMERGE (panel A, B) and RELIEF (panel C, D) patients. LPR patients were more frequently treated with PPI as monotherapy and with miscellany treatments, whereas GERD patients use more commonly PPI plus add-on, even though PPI alone are the first-choice therapy also in GERD. Considering the distribution of the new prescribed

**Figure 1.** Reflux Symptom Index (RSI) as median values for each single symptom in the EMERGE (no. 789) and in the

RELIEF population (no. 1934). Scores are reported as medians (bars) with lower and upper quartiles (boxes).

RFS, Reflux Finding Score. RFS > 7 suspect of laryngopharyngeal reflux (LPR).

**Table 3.** Reflux Finding Score.

Therefore, two large surveys were conducted in Italy: RELIEF, involving 86 otolaryngologists, and EMERGE, involving 56 gastroenterologists [54–56]. The aims of these surveys were: (1) to define clinical characteristics, including previous treatment, of the patients referred to consultation; (2) to evaluate the reliability of RFS, GIS, and RSI questionnaires in real-world settings, such as specialist office; and (3) to investigate the patients' perception of efficacy of the prescribed therapy, based on the best practice and considering also the new medical device.

The outcomes of these surveys are here presented and discussed. Now, we would draw the conclusive remarks from a pragmatic point of view. So, we compared the most relevant outcomes obtained by the two surveys.

First, we compared RSI questionnaires: at baseline, RSI questionnaire was filled by 1934 RELIEF patients and by 789 EMERGE patients. Globally, 594 (75.3%) EMERGE patients and 1250 (64.6%) RELIEF patients had positive RSI score. RSI values for each single symptom are analytically reported in **Figure 1**. The symptoms with the highest score were: heartburning, sensation of something sticking in the throat or a lump in the throat, and clearing throat, whereas breathing difficulties or choking episodes had the lowest score. The total score was 16 [14–20] in the EMERGE patients was significantly higher than in the RELIEFE patients: 16 [12–20] (p < 0.001; data not shown). Interestingly, RELIEF patients had significantly higher scores for some symptoms, including lump sensation, cough, dyspnea, hoarseness, and throat clearing, whereas EMERGE patients had higher scores for heartburn and difficult swallowing. So, the clinical features were really different in the two populations, such as GERD and LPR patients.

Considering the previous treatments, the frequency of past/current treatments in the EMERGE group (**Figure 2A**) was significantly higher than in RELIEF group (**Figure 2B**) patients (p< 0.0001): this outcome underlines the more intense recourse to medical therapy in GERD patients than in LPR patients. Analyzing the treatment options, **Figure 3** shows the distribution of different types of treatments prescribed in the past (panel A, C) or currently used (panel B, D): monotherapy with PPI, PPI in add-on, and Miscellany in EMERGE (panel A, B) and RELIEF (panel C, D) patients. LPR patients were more frequently treated with PPI as monotherapy and with miscellany treatments, whereas GERD patients use more commonly PPI plus add-on, even though PPI alone are the first-choice therapy also in GERD. Considering the distribution of the new prescribed

Therefore, two large surveys were conducted in Italy: RELIEF, involving 86 otolaryngologists, and EMERGE, involving 56 gastroenterologists [54–56]. The aims of these surveys were: (1) to define clinical characteristics, including previous treatment, of the patients referred to consultation; (2) to evaluate the reliability of RFS, GIS, and RSI questionnaires in real-world settings, such as specialist office; and (3) to investigate the patients' perception of efficacy of the prescribed therapy, based on the best practice and considering also the new medical device. The outcomes of these surveys are here presented and discussed. Now, we would draw the conclusive remarks from a pragmatic point of view. So, we compared the most relevant out-

Subglottic edema 0 = absent

Ventricular edema 2 = partial

Vocal-fold edema 1 = mild

Diffuse laryngeal edema 1 = mild

Posterior commissure hypertrophy 1 = mild

Granuloma/granulation tissue 0 = absent

Thicken laryngeal mucus 0 = absent

RFS, Reflux Finding Score. RFS > 7 suspect of laryngopharyngeal reflux (LPR).

Erythema/hyperemia 2 = arytenoids only

2 = present

4 = complete

4 = diffuse

2 = moderate 3 = severe 4 = polypoid

2 = moderate 3 = severe 4 = obstructing

2 = moderate 3 = severe 4 = obstructing

2 = present

2 = present

First, we compared RSI questionnaires: at baseline, RSI questionnaire was filled by 1934 RELIEF patients and by 789 EMERGE patients. Globally, 594 (75.3%) EMERGE patients and 1250

comes obtained by the two surveys.

**Table 3.** Reflux Finding Score.

56 Esophageal Cancer and Beyond

**Figure 1.** Reflux Symptom Index (RSI) as median values for each single symptom in the EMERGE (no. 789) and in the RELIEF population (no. 1934). Scores are reported as medians (bars) with lower and upper quartiles (boxes).

**Figure 2.** Distribution of the EMERGE (panel A) or RELIEF (panel B) patients according to the treatments: past, current, or never.

**Figure 4.** Distribution of the Marial® as monotherapy, PPI as monotherapy or PPI in add-on in new prescribed treatments

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**Figure 5.** Reduction in RSI values for each single symptom before and after a 4 week-treatment with Marial® as

monotherapy in EMERGE and in RELIEF patients.

(i.e., prescription during the visit) in EMERGE (panel A) and RELIEF (panel B) patients.

**Figure 3.** Distribution of different types of treatments prescribed in the past (panel A, C) or currently used (panel B, D): monotherapy with PPI, PPI in add-on, and miscellany in EMERGE (panel A, B) and RELIEF (panel C, D) patients.

treatments (i.e., prescriptions made during the visits) and specifically of Marial® as monotherapy, PPI as monotherapy or PPI in add-on, there was difference in EMERGE (**Figure 4A**) and in RELIEF (**Figure 4B**) patients (p < 0.0001): LPR patients were preferentially treated with Marial® alone, whereas GERD patients were treated essentially with PPI plus add-on.

The Clinical Relevance of Gastroesophageal Reflux Disease and Laryngopharyngeal Reflux… http://dx.doi.org/10.5772/intechopen.78357 59

**Figure 4.** Distribution of the Marial® as monotherapy, PPI as monotherapy or PPI in add-on in new prescribed treatments (i.e., prescription during the visit) in EMERGE (panel A) and RELIEF (panel B) patients.

**Figure 5.** Reduction in RSI values for each single symptom before and after a 4 week-treatment with Marial® as monotherapy in EMERGE and in RELIEF patients.

treatments (i.e., prescriptions made during the visits) and specifically of Marial® as monotherapy, PPI as monotherapy or PPI in add-on, there was difference in EMERGE (**Figure 4A**) and in RELIEF (**Figure 4B**) patients (p < 0.0001): LPR patients were preferentially treated with Marial®

**Figure 3.** Distribution of different types of treatments prescribed in the past (panel A, C) or currently used (panel B, D): monotherapy with PPI, PPI in add-on, and miscellany in EMERGE (panel A, B) and RELIEF (panel C, D) patients.

**Figure 2.** Distribution of the EMERGE (panel A) or RELIEF (panel B) patients according to the treatments: past, current,

or never.

58 Esophageal Cancer and Beyond

alone, whereas GERD patients were treated essentially with PPI plus add-on.

Comparing the patients' perception of treatment efficacy, reduction in RSI values for each single symptom before and after a 4 week-treatment with Marial® alone or with PPI in addon in EMERGE and RELIEF patients are reported in **Figures 5** and **6**. Marial® alone treatment induced a statistically significant higher reduction in each single symptom in RELIEF patients than in EMERGE patients, with the exception of heartburn, chest pain, indigestion, or stomach acid coming up (**Figure 5**). Similar results were obtained evaluating the reduction in RSI values in patients treated with PPI in add-on that was able to determine a higher statistically significant decrease in RELIEF than in EMERGE patients in each single symptom, with the exception of heartburn, chest pain, indigestion, or stomach acid coming up (**Figure 6**).

**Author details**

**References**

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Aragona Salvatore Emanuele1

\*Address all correspondence to: gio.cip@libero.it

2 Ospedale Policlinico San Martino, Genoa, Italy

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, Mereghetti Giada1

1 Center of Regenerative Medicine, Humanitas Mater Domini, Castellanza (VA), Italy

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\*

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In conclusion, these two surveys provided some interesting outcomes: (i) diagnostic questionnaires (RSI, RFS, and GIS) are reliable and useful both during the visit and to orient the treatment decision; (ii) GERD and LPR present different clinical features; (iii) as consequence the treatments (both previous and actual) are different; (iv) the introduction of Marial® significantly affected the otolaryngologist approach and partially the gastroenterologist orientation; (v) Marial® was effective both in LPR and GERD patients; (vi) Marial® showed more effectiveness than conventional therapy (PPI plus add-on); and (vii) LPR patients were more responsive to medical treatments than GERD patients. Therefore, these outcomes may give a pragmatic usefulness to both otolaryngologists and gastroenterologists in clinical practice.

**Figure 6.** Reduction in RSI values for each single symptom before and after a 4 week-treatment with PPI + add-on in EMERGE and in RELIEF patients.
