Between May 2011 and October 2011, 41 consecutive patients with LPS and an ENT diagnosis of LPR were prospectively enrolled in the study. During the first visit, a distinct investigator completed a structured interview on the patients, recording a careful medical history (with recording of height and weight), current medications, tobacco use and alcohol consumption. All patients signed a written informed consent form before entering into the study. The study was designed and carried out in accordance with the Helsinki Declaration (Sixth revision, Seul 2008).

Inclusion criteria were as follows: LPS for at least three consecutive months during the last year, previous history of dysphonia, cough, hoarseness, throat globe and/or dysphagia and an ENT diagnosis of LPR. In particular, such a diagnosis was performed after an accurate phoniatric and otorhinolaryngoiatric anamnesis and a general ENT examination with a flexible rhino-pharyngo-laryngoscope with an optical fibre. The reflux findings score (RFS) was completed by the otolaryngologist (RFS > 7), suggestive value for LPR), and all patients were asked to complete the reflux symptom index (RSI) (RSI > 13, suggestive value for LPR)[19]. Patients with a RSF > 7 and a RSI > 13 were considered affected by LPR.

Exclusion criteria were as follows: Previous surgery in the upper digestive tract, pregnancy and/or breastfeeding, eating disorders with vomiting, underlying psychiatric illness, use of non-steroidal anti-inflammatory drugs and aspirin, and peptic ulcer at a previous endoscopy.

All the enrolled patients were allowed an empirical treatment with PPIs for at least 8 wk, and the therapeutic outcome was recorded through a validated questionnaire (GERD impact scale, GIS), which was completed before and after therapy[20]. The GIS comprises eight questions about the frequency, over the previous 2 wk, of the following items: acid-related symptoms; chest pain; extra-esophageal symptoms; impact of symptoms on sleep, work, meals and social occasions; and the use of additional non-prescription medications. A 4-point rating Likert scale was used to describe the frequency of the symptoms over the previous 2 wk: 0 = none (absence of symptoms), 1 = mild (symptoms present for a little of the time), 2 = moderate (symptoms present for some of the time), and 3 = severe (symptoms present all of the time). Patients who responded with a score of 2 or 3 were considered as non-responders to PPI therapy.

The patients were also asked to rate their satisfaction with the symptom control on a global visual analogue scale (VAS) from 0 (no relief at all) to 10 (complete symptom relief). The VAS score has been used as a self-assessment tool for symptom measurement, which has been used in many other trials for evaluation of ENT symptoms and typical and atypical GERD symptoms[21,22].

After 8 wk of PPI therapy, all patients underwent upper endoscopy, stationary esophageal manometry and 24-h MII-pH esophageal monitoring. All patients discontinued PPI therapy at least 16 d before undergoing the planned esophageal investigations. The patients were only allowed to take alginates, on an as-needed basis, as rescue therapy. During upper gastrointestinal endoscopy, biopsies were taken from the gastric antrum and corpus to assess the presence of Helicobacter pylori and atrophic gastritis. Stationary manometry and MII-pH were performed after an overnight fast.

All subjects underwent stationary esophageal manometry to determine the distance of the proximal border of the lower esophageal sphincter (LES) from the nostrils and to evaluate the esophageal peristaltic wave. This study was performed by means of an eight-channel water-perfused manometric catheter with an external diameter of 4.5 mm (Dyno 2000^® Menfis, BioMedica, Bologna Italy), equipped with computer-based data recording and storage. Esophageal body motility and LES relaxation were tested by at least 10 wet swallows of 5 mL of water. Wave amplitude and duration were measured by means of four openings located at 5, 10, 15 and 20 cm above the LES. A stationary pull-through technique was then used to accurately locate the position of the LES.

MII-pH was performed using a polyvinyl catheter (diameter: 2.3 mm), equipped with an antimony pH electrode and several cylindrical electrodes, with a length of 4 mm, placed at intervals of approximately 2 cm (Sandhill Scientific Inc., Highland Ranch, CO). Each pair of adjacent electrodes represented an impedance-measuring segment corresponding to one recording channel. The single-use MII-pH catheter was positioned with the pH electrode 5 cm above the LES and the six impedance recording channels positioned at 3, 5, 7, 9, 15 and 17 cm above the LES.

The methodology of probe calibration, catheter placement, patient instruction and performance has been previously described[23].

At the end of the recording period, MII-pH tracings were reviewed manually to ensure accurate detection and classification of reflux episodes. Meal periods were excluded from the analysis. Impedance and pH data were used to determine the number and type of reflux episodes as well as the acid exposure time (AET) (reflux percent time) in each patient. In particular, the distal esophageal AET was defined as the total time with a pH measurement below 4 divided by the total time of monitoring. A percent time lower than 4.2% with pH < 4, over 24-h, was considered normal[23,24]. Reflux events were characterised according to previously reported criteria[25]. Total reflux number, esophageal AET and correlation between symptoms and reflux using the symptom index (SI) and symptom association probability (SAP) were evaluated for each patient as previously described[26]. The symptoms were considered to be related to reflux if they occurred within a 2-min time window after the onset of the reflux episode[27]. For symptom analysis, weakly acidic and weakly alkaline refluxes were pooled as non-acid reflux episodes (nadir pH > 4).

MII-pH data were matched with the ENT diagnosis. Statistical analysis was performed with the Chi-squared test and the Fisher exact test to evaluate nominal values, and Pearson’s correlation was performed to explore numerical values. The results were considered statistically significant for P values < 0.05.

The study evaluated 14 males and 27 females (M/F ratio 0.52), with a mean age ± SD of 51.5 ± 12.7 years and a mean body mass index of 25.7 ± 3.4 kg/m². Eight patients out of 41 (19.5%) were current smokers (5-10 cigarettes/d); 11/41 (28.8%) reported 2 to 3 units of alcohol consumption per day, and 33/41 (73.3%) drank two cups of coffee daily.

All subjects reported one or more LPS, and 25/41 patients also had typical GERD symptoms (heartburn and/or regurgitation). In particular, they described the predominant symptom (the most troublesome/frequent symptom during the day) and the overall most frequent symptoms in the last 6 mo. The predominant symptoms were globus 13 (31.7%), heartburn 10 (24.4%), hoarseness 9 (22%), sore throat 6 (14.6%), regurgitation 2 (4.9%) and epigastric pain 1 (2.4%). The overall most frequent symptoms were globus 21 (51.2%), heartburn 15 (36.6%), hoarseness 14 (34.1%), sore throat 13 (31.7%), regurgitation 9 (22%), dysphonia 9 (22%), belch 7 (17.1%), epigastric pain 5 (12.2%), and chronic cough 3 (7.3%).

The prevalence of symptom relief after PPI therapy, evaluated with the GIS questionnaire, showed that 10/41 (24.4%) patients reported at least one typical GERD symptom with “well controlled symptoms” (0) and that 23/41 (56.1%) patients reported only LPS without any symptom relief. All the details regarding the prevalence of symptom relief are described in Table 1.

The VAS analysis showed a significant reduction in typical GERD symptoms after PPI therapy. This reduction was not recorded for LPS. All details are presented in Table 2.

Upper endoscopy showed esophagitis (ERD) in 2/41 (4.9%) patients. None of the patients were diagnosed with complications of GERD (i.e., Barrett’s esophagus, stenosis, adenocarcinoma). No other lesion or mucosal abnormality was detected during the examination.

Endoscopic hiatal hernia was found in 17/41 (41.5%) patients. With regard to the histological findings of the corpus and antrum biopsies, 4 out of 41 (9.75%) patients had Helicobacter pylori infection, and no one had atrophic gastritis or intestinal metaplasia.

Two out of 41 (4.9%) patients presented with ineffective esophageal motility at the stationary manometry. Thirty-nine out of 41 (95.1%) patients did not present with abnormal esophageal motility.

The MII-pH analysis showed an abnormal AET in 5/41 (12.2%) patients [2 ERD and 3 non erosive esophagitis (NERD)]; 11/41 (26.8%) patients had a normal AET and a positive SAP (hypersensitive esophagus, HE), and; 25/41 patients had a normal AET and a negative association between symptoms and refluxes (no GERD patients). HE patients presented with a positive SAP for typical GERD-related symptoms (7 heartburn and 4 regurgitation).

The percentage of proximal reflux was abnormal (up more than 33%) in 4 cases with ERD/NERD (9.8%).

Gas refluxes were found more frequently in patients with globus (29.7 ± 3.6) and hoarseness (21.5 ± 7.4) than in patients with heartburn or regurgitation (7.8 ± 6.2). The SAP analysis for gas refluxes was positive for extra-esophageal symptoms.

The most frequent laryngoscopic findings in our selected patients, classified by our MII-pH results, are shown in Table 3. Overall, no differences were found among the three groups of patients in terms of the frequency of the laryngeal signs. In particular, both ERD and NERD patients did not show severe findings of laryngeal disease.

The differences observed among the three subgroups of patients (ERD/NERD, HE, no GERD) with esophageal pathophysiological analysis (MII-pH) were not demonstrated with the ENT symptom questionnaire (RSI) or with the laryngoscopic findings (RFS), as shown in Table 4.

A nominal (categorical) correlation (pathological vs non pathological) was performed considering endoscopic and esophageal pathophysiological examinations (results of endoscopy, MII-pH, AET value, total number of reflux events, number of proximal refluxes, gas refluxes, SAP). No match results were statistically significant. Only the number of gas refluxes was associated with the RFS (P = 0.028). The numerical correlation showed the same results: the correlation between the RFS and gas refluxes was confirmed (P = 0.026). All detailed results are shown in Table 5.

Laryngopharyngeal reflux is defined as the reflux of gastric contents into the larynx and pharynx, and it is the most extensively investigated extra-esophageal syndrome with an established association with gastroesophageal reflux disease (GERD). It may be manifested as laryngeal symptoms as well as laryngoscopic findings. However, laryngoscopic findings are not specific, and this largely limits their diagnostic value. Moreover, there are currently several controversies regarding accurate confirmation of such a diagnosis.

In the area of chronic laryngitis, the research hotspot is how to diagnose and manage laryngopharyngeal reflux (LPR). In particular, new diagnostic techniques to better understand the underlying pathophysiological mechanisms are necessary. Indeed, GERD may represent just one of the causes or an aggravating factor of laryngopharyngeal symptoms (LPS).

The use of esophageal multichannel impedance and pH technology has provided new insights into the complex pathogenesis underlying atypical reflux symptoms. In clinical practice, GERD is often considered to be the underlying cause of laryngeal symptoms, even in those patients who have a negative impedance and pH study or in those undergoing twice daily proton pump inhibitor therapy without any efficacy. In the present study, LPS were not always due to GERD, and laryngoscopic findings were not able to accurately identify patients with LPR due to GERD. Based on the findings, the only characteristic of refluxes associated with LPR was the presence of gas refluxes, although the mechanisms by which gas refluxes may contribute to LPR are far from being clarified. Overall, patients with typical reflux symptoms and abnormal acid exposure time had increased symptom relief after proton pump inhibitor therapy. Conversely, extra-esophageal reflux-suspected symptoms were less responsive to antisecretive therapy.

The present study underscores the importance of impedance and pH monitoring to assess the presence of an established association between GERD and suspected LPR.

Extra-esophageal syndromes: The manifestations of GERD have been recently classified into either esophageal or extra-esophageal syndromes. Among the latter, the atypical manifestations of GERD such as chronic cough and LPS (i.e., laryngitis, globus, throat discomfort) have been included; Laryngopharyngeal reflux: Laryngopharyngeal reflux is a condition with an established association with GERD and is defined as the reflux of gastric contents into the larynx and pharynx; Multichannel intraluminal impedance and pH monitoring: This is a technique that is able to detect both acid and non-acid reflux and proximal migration of the refluxate, to physically characterise the refluxate (i.e., liquid, gas, mixed), and to correlate symptoms with each type of reflux.

This is an interesting and well-structured study aimed to evaluate the diagnostic capacity of laryngoscopic findings suspected to be related to GERD, as performed by ear, nose and throat physicians. The LPR definition is based on the symptoms, although the criteria for LPR symptoms have not been established by many papers. The entry number is relatively small. The authors use multichannel intraluminal impedance and pH monitoring and many questionnaires as the diagnostic gold standard. Of note, they found that laryngoscopic findings had a poor sensitivity and were not related to the multichannel intraluminal impedance and pH results. From their data, the authors suggested that another reason for LPR besides acid reflux was gas reflux.