Calabrese F, Pasta A, Bodini G, Furnari M, Zentilin P, Giannini EG, et al. Applying Lyon consensus criteria in the work-up of patients with extra-oesophageal symptoms – A multicentre retrospective study. Aliment Pharmacol Ther. 2024;59:1134–1143.

Популярно о болезнях ЖКТ Лекарства при болезнях ЖКТ Если лечение не помогает Адреса клиник

Авторы: Calabrese F. / Pasta A. / Bodini G. / Furnari M. / Zentilin P. / Giannini E.G. / Maniero D. / Della Casa D. / Cataudella G. / Frazzoni M. / Penagini R. / Arsiè E. / de Bortoli N. / Visaggi P. / Savarino V. / Savarino E.V. / Marabotto E.


Applying Lyon consensus criteria in the work-up of patients with extra-oesophageal symptoms – A multicentre retrospective study


Francesco Calabrese1,2, Andrea Pasta1, Giorgia Bodini1,2, Manuele Furnari1,2,
Patrizia Zentilin1,2, Edoardo G. Giannini1,2, Daria Maniero3, Domenico Della Casa4,
Giovanni Cataudella5, Marzio Frazzoni6, Roberto Penagini7,8, Arsiè Elena7,8,
Nicola de Bortoli9, Pierfrancesco Visaggi9, Vincenzo Savarino1, Edoardo Savarino3, Elisa Marabotto1,2


1 Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy
2 IRCCS Policlinico San Martino, Genoa, Italy
3 Gastroenterology Unit, Azienda Ospedale Università di Padova, Padua, Italy
4 Department of Surgical-Surgery Endoscopy, Spedali Civili, University of Brescia, Brescia, Italy
5 Gastroenterology and Endoscopy Unit, San Bortolo Hospital, Vicenza, Italy
6 Digestive Pathophysiology Unit, Baggiovara Hospital, Modena, Italy
7 Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
8 Department of Pathophysiology and Transplantation, Università degli Studi, Milan, Italy
9 Gastrointestinal Unit-Department of Translational Sciences and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

Correspondence Elisa Marabotto, Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa 16132, Italy. Email: elisa.marabotto@unige.it


Summary

Background
: The diagnosis of gastro-oesophageal reflux disease (GERD) based on otolaryngologist's assessment of laryngoscopic findings remains contentious in terms of sensitivity and specificity.

Aims: To evaluate GERD prevalence, applying Lyon 2.0 Consensus criteria, in patients with extra-oesophageal symptoms undergoing laryngoscopic examination and impedance-pH monitoring.

Methods: In this retrospective assessment, we included 470 patients with extra-oesophageal symptoms, either isolated or combined with typical symptoms, who had been referred to six tertiary Italian Gastroenterology Units between January and December 2020. Of these, 274 underwent 24-h impedance-pH monitoring and laryngoscopy off PPI therapy. GERD diagnosis followed Lyon Consensus 2.0 criteria, incorporating mean nocturnal baseline impedance when pH-impedance monitoring was inconclusive.

Results: Laryngoscopic examination revealed pathological findings (predominantly posterior laryngitis) in 71.2% (195/274). GERD was diagnosed in 29.2% (80/274) via impedance-pH monitoring. The prevalence of GERD in patients with positive or negative laryngoscopy was similar (32.3% vs. 21.5%, p = 0.075). No significant difference in proximal reflux occurrences was noted between positive and negative laryngoscopy groups (33.3% vs. 24.1%, p = 0.133). Laryngoscopy demonstrated sensitivity and specificity of 78.8% and 32.0%, respectively, with a positive predictive value (PPV) of 32.3% and negative predictive value (NPV) of 28.4%. In contrast, a threshold of four concurrent laryngoscopic signs, identified in only eight patients, demonstrated a PPV of 93.8% and a NPV of 73.6% (sensitivity 25.4%, specificity 99.2%).

Conclusion: This study underscores the limited diagnostic accuracy of laryngoscopy, emphasising the necessity of impedance-pH monitoring for confirming GERD diagnoses using Lyon 2.0 criteria in patients with suspected extra-oesophageal symptoms.


1 | BACKGROUND

Gastro-oesophageal reflux disease (GERD) is highly prevalent worldwide with an approximate rate of 20%. [1,2] The Montreal classification states that GERD is a condition developing when the reflux of gastric contents causes symptoms and/or complications. [3] GERD is characterised by a heterogeneous group of clinical manifestations including typical and extra-oesophageal symptoms. In the last decades the prevalence of extra-oesophageal symptoms (EES) of GERD seems to be increased. [4–7] Several EES have been attributed to GERD, but only few of them have shown a strong cause-effect association (e.g. asthma, chronic cough and hoarseness). [8–11] The pathophysiology underlying the development of EES is not fully understood, and several mechanisms have been hypothesized. Laryngeal structures appear very sensitive to acid and pepsin and small amounts of them can determine mucosal inflammation. [12] Some authors have suggested an alternative indirect mechanism causing EES in patients with GERD. [13–16] This theory, named the ‘reflex theory’, describes the distal oesophageal reflux as a trigger for vasovagal reflex pathway, resulting in EES (especially cough and asthma). [16] Some authors have also highlighted the role of the upper oesophageal sphincter (UES) incompetence and abnormal oesophageal motility in the pathophysiology of EES. [12,17–19 ]

Patients with EES suspected for GERD are frequently referred to Gastroenterologists after Ear-Nose-Throat (ENT) evaluation. Indeed, laryngeal findings, such as posterior laryngitis, laryngeal erythema or hyperaemia, vocal fold oedema, commissure hypertrophy, thick endo-laryngeal mucus, infra-glottic oedema, granuloma or granulation, ventricular obliteration and diffuse laryngeal oedema, are often considered as GERD-related signs by ENT specialists, with the following suggestion of starting PPI treatment. [20–24] Nevertheless, at least one of those features could be found in up to 86% or 93% of healthy volunteers, as reported respectively by Hicks et al and Powell et al [25,26] To overcome this limitation, Belafsky et al [27] proposed the ‘Reflux Finding Score’ (RFS) in order to increase the diagnostic accuracy of the laryngoscopic evaluation. Unfortunately, the sensitivity and specificity of RFS appear low, [26,28] while Branski et al [28] have demonstrated how the ENT endoscopic examination could be influenced by inter-observer interpretation. Thus, the identification of patients with actual laryngo-oesophageal reflux disease (LPRD) among those with EES and pathological laryngoscopic examination remains a significant clinical challenge. [11–19]

Over the last years, an important body of knowledge has enhanced our understanding on the pathophysiology and diagnosis of GERD. [21] In particular, the refinement of impedance-pH metrics has increased the sensitivity and specificity of this functional technique.[21,22] In this regards, an important advantage has been represented by the development and validation of distal mean nocturnal baseline impedance (MNBI) as a measure of mucosal permeability and therefore oesophageal mucosal damage, while Post-reflux Swallow-induced Peristaltic Wave Index (PSPW-I) as a measure of chemical clearance has been lately removed from adjunctive evidence of GERD in Lyon consensus 2.0. [21–23] The increasing experience on these new parameters, together with the established findings from histology and motility as assessed by high resolution manometry (HRM) in patients with GERD, has changed the modern definition of this disease, leading the group of experts involved in the Lyon Consensus to classify GERD on the basis of traditional parameters, that is acid exposure time (AET) and endoscopic appearance, with the addition of modern features, such as MNBI, number of reflux episodes and innovative histologic alterations, such as the dilation of intercellular spaces (DIS), in order to narrowing down the rate of patients with an unclear diagnosis of GERD.

The aim of our study was to assess the prevalence of GERD diagnosis according to Lyon Consensus 2.0 criteria in patients with EES and a pathological laryngoscopic examination, using impedance-pH monitoring and applying the last Lyon 2.0 criteria. We have also tried to define the accuracy of laryngoscopic examination in this group of patients.

2 | MATERIALS AND METHODS

This was a retrospective, multicentre study, which involved six Italian tertiary centres. We selected patients with EES, combined or not with typical symptoms, referred to our Gastroenterology Units between January and December 2020. We included patients with laryngo-oesophageal symptoms persisting for at least 3 months and with at least two episodes per week. All the symptoms were weighted and reported by the referral gastroenterologist physician during the outpatient visit. We considered the following aspects for the purpose of this study: chest pain, clearing voice, cough, dysphonia, globus, heartburn, hoarseness, oral pyrosis, post nasal drip and regurgitation. Main symptom was considered as the most significant symptom for the patient and the first to lead to medical attention.

A previous response to empirical 8-week proton pump inhibitor (PPI) treatment, assessed by asking patients about their satisfaction with symptom control, was not an exclusion criteria. Only patients who underwent both 24-h impedance-pH monitoring off-therapy and laryngoscopy at the same time were enrolled (Figure 1). Patients with previous history of upper gastrointestinal surgery (included bariatric surgery), history of peptic ulcer, history of laryngeal, pharynx, oral or oesophageal cancer, severe acute illness, psychiatric illness (included eating disorders) were not included in the study.

FIGURE 1. Flow chart of our study design and patients included in former analysis.


The single-use multichannel intraluminal impedance (MII)-pH catheter was placed transnasally into the oesophagus. The pH electrode was positioned 5 cm above the upper margin of the lower oesophageal sphincter (LES), [29] assessed previously with HRM. The tracing analysis was conducted using ZepHr® Impedance/pH Reflux Monitoring System featuring Zvu® Functional GI Software (Diversatech Healthcare). Diagnosis of GERD was made according to the criteria of Lyon Consensus 2.0, considering the exam positive if acid exposure time (AET) was >6; diagnosis of GERD was excluded if AET was <4. Inconclusive results (AET between 4 and 6) were further analysed using the novel impedance metrics and the number of total refluxes in order to add confidence to diagnosis of GERD. [21] A number of total refluxes above 80 was considered to diagnose GERD in patients with AET between 4 and 6. The inconclusive tests who had a MBNI < 1500 ohm at the impedance measuring segment located at 5 cm above the LES were defined positive for GERD. Additionally, we assessed MNBI again from the most distal impedance channel for three periods of 10 min cumbent phase. The mean baseline for each 10 min period (except pH drops, refluxes and swallowing events) was quantified by the software, and then we have manually calculated the mean of the three measurements, thus precisely obtaining MNBI. [30,31] Patients with a diagnosis of hypersensitive oesophagus were excluded (normal AET, normal number of refluxes, SI and SAP positive). We used SI and SAP thresholds to be considered positive as 50% and 95% respectively. [21,22] Proximal refluxes over 42.6% were considered abnormal, according to Zentilin et al. [32 ]

All findings were retrospectively evaluated and patients' anonymity was preserved.

2.1 | Statistical analysis

Statistical analysis was performed using IBM SPSS Statistics, Release Version 25.0 (SPSS, Inc., 2017, Chicago, IL, USA, www. spss. com). Kolmogorov–Smirnov analysis was performed to test the normality of variables. Results of continuous variables were expressed as median and interquartile range (IQR). For ordinal and nominal variables, contingency tables indicating frequency and percentage in the studied population were used. For the comparison of continuous variables between different groups of patients, non-parametric tests of Kruskal–Wallis or Mann–Whitney were used, when appropriate. Nominal variables were examined with the Pearson chi square (χ2) test and with Spearman's rank correlation index for correlating continuous variables. ROC curves were used to determine the cut-off and predictive value of laryngoscopic examinations in identifying GERD patients.

3 | RESULTS

3.1 | General characteristics of patients underwent laryngoscopic assessment


We evaluated 470 patients, all of them aged >18 years. Laryngoscopic examination was not available in 203 patients and for this reason they were excluded from the study. A total of 274 subjects were eligible and included in our analysis (Figure 1). The median age was 55 years (IQR: 45–65 years) and males enrolled were 103/274 (37.6%). The most frequent symptom was chronic cough (n = 90/274, 32.8%), followed by globus (40/274, 14.6%) and need of clearing voice (37/274, 13.5%). Detailed demographic, anthropometric and clinical characteristics of our patients are shown in Table 1. The group of excluded patients, nonetheless, was analysed and used as comparison group. It was observed that the two groups were homogeneous as to gender, age, AET and total number of refluxes. On the contrary, smoking habit was more common in patients who did not undergo laryngoscopy than in the study population (50/203, 25.9% vs. 254/274, 7.9%, p < 0.001), as well as the formers had higher BMI (26.0 vs. 24.6, p = 0.026). Upper endoscopy was available in 269 patients and only 5 of them had grade B esophagitis (1.8%), all of them with a definitive diagnosis of GERD according to their impedance-pH monitoring examination.


TABLE 1. Patient's characteristics and main symptoms subdivided between those who underwent or not laryngoscopy.

Parameters

Patients who did not undergo
laryngoscopy N = 193
Patients underwent
laryngoscopy N = 274
p-value*

Gender (M/F) [n, %]
71 (36.8%)/122 (63.2%)103 (37.6%)/171 (62.4%)0.860
Age [years]
54 (43–65)55 (45–65)0.262
BMI [kg/m2]
26 (22.2–29)24.6 (22.4–27.6)0.026
Active smokers [n, %]
50 (25.9%)20 (7.3%)<0.001
Main symptom [n, %]
Chest pain3 (1.6%)0 (0%)0.400
Clearing voice14 (7.3%)37 (13.5%)0.540
Cough68 (35.2%)90 (32.8%)1
Dysphonia13 (6.7%)23 (8.4%)1
Globus44 (22.8%)40 (14.6%)0.600
Heartburn18 (9.3%)31 (11.3%)1
Hoarseness4 (2.1%)35 (12.8%)0.01
Oral pyrosis4 (2.1%)5 (1.8%)1
Post nasal drip2 (1.0%)8 (2.9%)1
Regurgitation23 (11.9%)5 (1.8%)<0.001
AET [%]
1.6 (0.4–5.0)1.9 (0.6–4.4)0.919
No. of refluxes [n, %]
44 (25–65)41 (21–66)0.385

Note: Continuous data are median (IQR) and nominal data are number (% patients).
Abbreviations: AET, acid exposure time; BMI, body mass index.
*p-value assessed with Pearson's chi-squared test or Mann–Whitney U test for nominal and continuous variables respectively. p-values are adjusted for multiple comparisons with Bonferroni correction.



3.2 | Laryngoscopy and pH impedance findings

Overall, 195/274 patients had positive laryngoscopy and GERD was diagnosed in 80/274 patients (29.2%) on impedance-pH monitoring. In detail, diagnosis was made based on AET > 6 in 41/80 patients (51.2%). Regarding subjects with inconclusive GERD diagnosis (AET between 4 and 6), diagnosis was made according to number of total refluxes >80 in 22/80 (27.5%), a positive SI and SAP in 4/80 (5.0%) and a MNBI < 1500 in 13/80 (16.3%). Table 2 shows demographic data and main symptoms in patients divided into positive or negative laryngoscopy. The prevalence of GERD in patients with and without positive laryngoscopy examination was not statistically significant (63/195, 32.3% vs. 17/79, 21.5% with p = 0.075).


TABLE 2. Patient's characteristics and main symptoms subdivided between those with positive or negative laryngoscopy.

Parameters

Negative laryngoscopy
exam N = 79
Positive laryngoscopy
exam N = 195
p-value*

Gender (M/F) [n, %]
71 (36.8%)/122 (63.2%)68 (34.9%)/127 (65.1%)0.144
Age [years]
55 (45–67)55 (45–65)0.653
BMI [kg/m2]
24 (22–27)25 (22.8–28)0.080
Active smokers [n, %]
2 (2.5%)18 (9.2%)0.053
Main symptom [n, %]
Clearing voice7 (8.9%)30 (15.4%)1
Cough24 (30.4%)66 (33.8%)1
Dysphonia5 (6.3%)18 (9.2%)1
Globus17 (21.5%)23 (11.8%)0.711
Heartburn10 (12.7%)21 (10.8%)1
Hoarseness11 (13.9%)24 (12.3%)1
Oral pyrosis1 (1.3%)4 (2.1%)1
Post nasal drip3 (3.8%)5 (2.6%)1
Regurgitation1 (1.3%)4 (2.1%)1
AET [%]
1.4 (0.3–2.9)2 (0.9–5.0)0.006
No. of refluxes [n, %]
36 (15–65)42 (22–68)0.133

Note: Continuous data are median (IQR) and nominal data are number (% patients).
Abbreviations: AET, acid exposure time; BMI, body mass index; GERD, gastro-oesophageal reflux disease.
*p-value assessed with Pearson's chi-squared test or Mann–Whitney U test for nominal and continuous variables respectively. p-values are adjusted for multiple comparisons with Bonferroni correction.


AET was significantly higher when laryngoscopic examination was pathological (6, IQR: 4.8–10.9 vs. 4.9, IQR 2.9–6, p = 0.028), whereas no differences in total number of refluxes were found in GERD patients (81, IQR: 61–96 vs. 88, IQR: 69–99, p = 0.525). No difference in the number of proximal refluxes was observed in patients with positive or negative laryngoscopy (65/195, 33.3% vs. 19/79, 24.1%; p = 0.133). Sensitivity (SE) and specificity (SP) of laryngoscopy in diagnosing GERD was 78.8% and 32.0%, respectively in AUROC analysis (PPV = 32.3%; NPV = 28.4%).

At least one pathological feature reported in Table 3 was found in 195 patients among 274 subjects evaluated with laryngoscopy. The most common finding was posterior laryngitis (n = 145/195, 74.4%), followed by laryngeal erythema or hyperaemia (n = 99/195, 50.8%) and diffuse laryngeal oedema (n = 56/195, 28.7%). GERD diagnosis was significantly associated with infra-glottic oedema (r = 0.291, p < 0.001), ventricular obliteration (r = 0.266, p < 0.001), thick endo-laryngeal mucus (r = 0.217, p = 0.002), posterior commissure hypertrophy (r = 0.267, p < 0.001), vocal fold oedema (r = 0.223, p = 0.002), erythema/ hyperaemia (r = 0.307, p < 0.001) and diffuse laryngeal oedema (r = 0.337, p < 0.001). No statistical association was found between GERD and posterior laryngitis and granuloma/granulation (Table 3).


TABLE 3. Laryngeal features in GERD and non-GERD patients.

Non-GERDGERDp-value*
Infragloctic oedema6 (4.5%)15 (23.8%)<0.001
Ventricular obliteration1 (0.8%)8 (12.7%)<0.001
Erythema/hyperaemia53 (40.2%)46 (73.0%)<0.001
Vocal fold oedema9 (6.8%)14 (22.2%)0.002
Diffuse laryngeal oedema24 (18.2%)32 (50.8%)<0.001
Posterior commissure hypertrophy19 (14.4%)24 (38.1%)<0.001
Granuloma/granulation2 (1.5%)3 (4.8%)0.182
Thick endolaryngeal mucus7 (5.3%)12 (19.0%)0.002
Posterior laryngitis102 (77.3%)43 (68.3%)0.179

*p-value assessed with Pearson's chi-squared test and adjusted for multiple comparisons with Bonferroni correction.


AUROC analysis of laryngeal pathological signs that can permit the identification of GERD patients is reported in Figure 2 (AUC: 0.76, CI 95%: 0.68–0.83, p < 0.001). A cut-off value of 2 signs showed a PPV of 54.3% and NPV of 80.0% (SE = 60.3%, SP = 75.8%). Conversely, a cut-off of three signs showed a PPV of 61.5% and NPV of 75.0% (SE: 38.1%, SP = 88.6%).

FIGURE 2. ROC analysis of the number of laryngeal pathological signs able to predict GERD diagnosis. Panel A shows the area under ROC, while panel B and the lower table show sensitivity, specificity, NPV and PPV for different cut-off values in relation to the number of laryngeal pathological signs. LR, likelihood ratio; NPV, negative predictive value; PPV, positive predictive value; Se, sensitivity; Sp, specificity.


3.3 | Symptoms and PPI response

The main symptoms and general characteristics for both GERD and non-GERD patients are presented in Table 4, whereas Figure 3 illustrates the prevalence of each symptom, encompassing both main and secondary symptoms. Overall, 196 patients experienced only EES, while 78 patients showed typical symptoms associated. After 8-week PPI therapy, 44/274 (16.1%) patients had relief of their main symptoms. The response to treatment was greater in patients with combined typical symptoms than in those with extra-oesophageal ones, in particular regurgitation 4/5 (80%) and heartburn 16/31 (51.6%) vs oral pyrosis 1/5 (20%), globus 7/39 (17.9%), cough 11/89 (12.4%), dysphonia 2/22 (9.1%), hoarseness 2/34 (5.9%), clearing voice 1/37 (2.7%) and post nasal drip 0/8 (0%). Of the 195 patients with positive laryngoscopy treated with PPI, 34 of them reported clinical response (PPV = 17.4%), while of the 80 patients diagnosed with GERD after 24-h impedance-pH monitoring according to Lyon criteria, 30 had clinical response to PPI therapy (PPV = 37.4%) (Table 5).


TABLE 4. Patient's main symptoms according to the presence or exclusion of GERD.

GERD N = 80Non-GERD N = 194p-value*
Gender (M/F) [n, %]
28 (35.0%)/52 (65.0%)75 (38.7%)/119 (61.3%)0.57
Age [years]
55 (44–64)56 (45–66)0.95
BMI [kg/m2]
24 (22.2–27.1)24.8 (22.6–27.8)0.84
Active smokers [n, %]
2 (2.5%)18 (9.2%)0.06
Typical and atypical symptoms [n, %] 20 (25.0%)58 (29.9%)0.46
Main symptom [n, %]
Chest pain0 (0%)0 (0%)NA
Clearing voice8 (10%)29 (14.9%)1
Cough26 (32.5%)64 (33.0%)1
Dysphonia7 (8.7%)16 (8.2%)1
Globus16 (20.0%)24 (12.4%)1
Heartburn4 (5%)27 (13.9%)0.45
Hoarseness16 (20.0%)19 (9.8%)0.42
Oral pyrosis0 (0%)5 (2.5%)1
Post nasal drip2 (2.5%)6 (3.1%)1
Regurgitation1 (1.3%)4 (2.1%)1

*p-value assessed with Pearson's chi-squared test and adjusted for multiple comparisons with Bonferroni correction.



TABLE 5. Laryngeal features according to the clinical response after PPI therapy.

ResponderNon-responderp-value*
Infragloctic oedema [n, %]3 (16.7)18 (11.2)1
Ventricular obliteration [n, %]09 (5.6)1
Erythema/hyperaemia [n, %]11 (57.9)88 (54.0)1
Vocal fold oedema [n, %]3 (15.8)20 (14.3)1
Diffuse laryngeal oedema [n, %]4 (21.1)52 (35.1)1
Posterior commissure hypertrophy [n, %]4 (21.1)39 (26.7)1
Granuloma/granulation [n, %]1 (5.3)4 (2.9)1
Thick endolaryngeal mucus [n, %]2 (10.5)17 (12.1)1
Posterior laryngitis [n, %]32 (76.2)112 (57.4)0.216

*p-value assessed with Pearson's chi-squared test and adjusted for multiple comparisons with Bonferroni correction.


4 | DISCUSSION

FIGURE 3. Histogram of all main and secondary
symptoms reported by all patients.




Patients with EES represent a diagnostic and therapeutic challenge in clinical practice, particularly in the hospital-based setting. Indeed, the diagnosis of GERD is often suspected by ENT and other specialists according to laryngoscopic findings, but the frequently observed lack of oesophageal mucosal injuries at upper endoscopy and the limited response to anti-reflux medical treatment pose more questions than answers on whether these patients should be truly identified as GERD subjects. Thus, the main aim of this study was to confirm GERD diagnosis in patients with EES, assessing its prevalence using the 24-h impedance-pH monitoring in according to Lyon criteria 2.0, which represent current gold standard for GERD diagnosis. We also tried to evaluate the accuracy of laryngoscopy in this setting of patients.

Gastro-oesophageal reflux disease is one of the most common gastrointestinal diseases worldwide and develops when the backflow of gastric contents into the oesophagus causes troublesome symptoms or mucosal damage. [3,33] Its prevalence in our study population was 29.2%, slightly higher than the European estimated prevalence (9%–26%), probably due to the collection of patients referred to tertiary centres and the symptomatic cohort. [34]

The prevalence of GERD observed by Patel et al. was higher in this population, standing at 50%. This difference could be due to the significantly higher BMI in Patel's patients compared to ours and their predominantly American origin, reflecting differences in diet and lifestyle between the two populations. Furthermore, the use of the 48-hour wireless pH monitoring method could contribute to a more accurate detection of reflux episodes, potentially explaining the higher GERD prevalence reported by Patel et al. [35]

Assessing the prevalence of GERD in patients complaining EES has traditionally been influenced by studies reporting referral and selection bias. Jaspersen et al. in the proGERD study tried to overcome this limit in a prospective large cohort and the rate of GERD in EES was found out to be 32.8%, according to the previous epidemiological evaluation of El-Seragh et al [4,36] in United States Military Veterans.

Several EES or so-called ‘extra-oesophageal symptoms’ are usually attributed to GERD, but these symptoms and also laryngeal signs are not specific. [4] The most common EES reported in literature are hoarseness (14.8%) and asthma (4.8%–9.3%). Chronic cough is reported to be associated with GERD in 10%–59% of the cases, however, in heterogeneous studies. [4,14,37–41] Lyon 2 .0 Consensus recommends a pulmonary evaluation for chronic cough, nevertheless in our study cough was consistently accompanied by other ENT symptoms, thus justifying a laryngoscopic examination. [21] To improve diagnostic sensitivity and specificity, several tests have been proposed in this setting of patients: the salivary pepsin test (Peptest), the evaluation of proximal acid oesophageal exposure (Restech), the Dx-pH measurement system, the evaluation of Mucosal Impedance (MI), the assessment of Hypopharyngeal-Oesophageal Multichannel Intraluminal Impedance-pH (HEMII-pH) and the impedance-pH monitoring. Some of these tests still suffer from several limits, such as poor sensitivity, weak reproducibility, and risk of swallow-related artefacts, thus they are not validated. [7,8,11,42–50] Notably, additional metrics of impedance- pH, such as MBNI and SI or SAP, have contributed in the last years to increase the detection of GERD patients and to discriminate different phenotypes in the general GERD population, thus contributing to define this examination as the best tool to diagnose GERD in this kind of patients; However, the utility of SI and SAP in assessing some ENT symptom may be limited due to challenges in accurately determining the onset of these symptoms. [21,22] The role of upper endoscopy in diagnosing GERD with EES is limited. It could be helpful in discovering Erosive Reflux Disease (ERD), but this condition is reported to be present only in 30% of PPI-naive patients complaining heartburn. [29] According to Lyon Consensus 2.0 criteria, GERD can be defined after an endoscopic evaluation only if grade B, C or D esophagitis, peptic stricture or histology proven Barrett's mucosa >1 cm are encountered. [21,51] Even adding biopsies, endoscopy still remains not useful in diagnosing GERD in patients with EES, as underlined by Koufman et al. [38,39] Moreover, currently the majority of patients who undergo endoscopic assessment take PPIs before the test further limiting the reliability and utility of this test in identifying patients with definite GERD. [21] Thus, it is difficult to use endoscopy alone as a diagnostic method for diagnosing GERD. In the last decades, more laryngoscopic abnormal signs were evaluated as potential markers of GERD. However, as reported by Vaezi et al, [24] some of these findings are related to smoke and alcohol habits, allergies or asthma, voice abuse or viral illness. In previous studies, laryngeal erythema and oedema are reported as the most frequent signs related to GERD, but posterior laryngitis was the most common abnormal laryngeal finding in our group of patients (74.4%). [52,53] In medical literature, up to 50% of patients with abnormal laryngeal features have negative pH monitoring and an even higher prevalence was found in our study (67.7%). [53 ]

In our study, the accuracy of laryngoscopy in diagnosing GERD is poor, in particular we have found a positive predictive value of 32.3% and a specificity of 32% when only one laryngeal pathological finding is reported. On the other hand, the specificity and sensitivity of the test increase proportionally with the sum of positive features. Thus, we think that a cut-off of at least 4 laryngeal signs could make laryngoscopy a reliable exam for considering LRPD as an appropriate diagnosis in patients with EES (Figure 2). However, this scenario could be found only in a small proportion of the population (5.6% according to our data) and therefore the diagnostic yield of laryngoscopy appears to be very low.

Focusing on pH-impedance exam, the AET was greater in patients with positive than negative laryngoscopy (1.4% vs. 2.0%, p = 0.006), suggesting a potential association with acid. Our study confirms the pathophysiological complexity of LRPD even analysing the height of proximal refluxes by impedance-pH monitoring, which are expected to be higher in case of laryngoscopic signs of inflammation.[54] Indeed, no statistical difference was found in terms of number of proximal refluxes between patients with positive or negative laryngoscopy, as well as of number of total refluxes.

In our study population we found that chronic cough was the most common symptom (32.8%) reported by patients referred to tertiary centres for further investigation on the potential association of this symptom with GERD, followed by globus (14.6%) and need of clearing voice (13.5%). In most of the subjects there is a weak association between the main EES and GERD proved by impedance-pH testing, thus we believe that relying on just one symptom could mislead clinician's judgement. Therefore, the main challenge of identifying patients with GERD among the wide number of subjects reporting laryngo-oesophageal symptoms remains unanswered.

Finally, we have observed a better clinical response to PPI therapy in patients with concomitant typical symptoms. Williams et al [55] have found a poor clinical response to PPI therapy in patients with laryngitis attributed to GERD by ENT physicians (47% and 63%, at 6 and 12 weeks, respectively). In our study the diagnosis of GERD according to Lyon criteria in patients with atypical GERD symptoms predicted a better response with PPI therapy comparing to those diagnosed according to laryngoscopic exam (37.4% vs. 17.4%, respectively). On this regard, we agree with the opinion of Vaezi et al [53] who questioned the possibility that this relatively good result was due to a wrong diagnosis. Indeed, the coexistence of GERD and EES does not establish a direct causal relationship, highlighting the intricate complexities that contribute to the limited response of EES patients to PPI therapy, even in proven GERD.

This study has some limitations since it is retrospective and only patients referred to tertiary centres were recruited. Moreover, the laryngoscopic examination was made by different ENT physicians and the tools may differ in different centres. The strengths of our study are that the population we recruited is large and different diagnostic tests have been adopted (endoscopy, laryngoscopy and impedance-pH monitoring) to confirm the existence of a real GERD with EES. Nevertheless, this is the largest population of suspected GERD patients with EES evaluated comparing both laryngoscopy and impedance-pH monitoring. Our findings appear to be particularly relevant in reconsidering the clinical value of abnormal laryngeal features during laryngoscopic examination and their association with GERD.

In conclusion, laryngoscopic examination may be a useful test in patients with EES in order to exclude possible neoplastic causes, but it can help in diagnosing GERD only when at least 4 abnormal signs are simultaneously detected during this examination. On that account, few laryngoscopic features could only pose a suspect of an underlying GERD, but its diagnosis would still need to be confirmed by impedance-pH monitoring as recommend by Lyon 2.0 consensus before starting a long-term pharmacological treatment.

AUTHOR CONTRIBUTIONS

Francesco Calabrese: Conceptualization; investigation; writing – original draft; methodology; validation; visualization; writing – review and editing; data curation; resources; project administration. Andrea Pasta: Investigation; methodology; validation; visualization; software; formal analysis; data curation; supervision; writing – review and editing. Giorgia Bodini: Writing – review and editing. Manuele Furnari: Writing – review and editing. Patrizia Zentilin: Writing – review and editing. Edoardo G. Giannini: Writing – review and editing; visualization; validation; methodology; supervision. Daria Maniero: Writing – review and editing; data curation. Domenico Della Casa: Writing – review and editing; data curation. Giovanni Cataudella: Writing – review and editing; data curation. Marzio Frazzoni: Writing – review and editing; data curation. Roberto Penagini: Data curation; writing – review and editing. Elena Arsiè: Writing – review and editing; data curation. Nicola de Bortoli: Writing – review and editing. Pierfrancesco Visaggi: Writing – review and editing. Vincenzo Savarino: Writing – review and editing. Edoardo Vincenzo Savarino: Writing – review and editing; supervision; visualization; methodology. Elisa Marabotto: Conceptualization; investigation; writing – original draft; methodology; validation; visualization; writing – review and editing; project administration; supervision; data curation.

The Handling Editor for this article was Professor Dr Colin Howden, and it was accepted for publication after full peer-review.

Elisa Marabotto and Francesco Calabrese express their gratitude to all co-authors and their respective institutions for their invaluable contributions to the development of this manuscript. This study received no financial support.

ACKNOWLEDGEMENTS

The authors have nothing to report.

FUNDING INFORMATION

The study was conducted without any financial support.

CONFLICT OF INTEREST STATEMENT

None to declare for this article.

ORCID

Francesco Calabrese https://orcid.org/0009-0008-4706-1499
Edoardo G. Giannini https://orcid.org/0000-0001-8526-837X
Marzio Frazzoni https://orcid.org/0000-0002-8608-1563
Roberto Penagini https://orcid.org/0000-0001-6918-9479
Nicola de Bortoli https://orcid.org/0000-0003-1995-1060
Pierfrancesco Visaggi https://orcid.org/0000-0002-6985-5301
Vincenzo Savarino https://orcid.org/0000-0001-6803-1952

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How to cite this article: Calabrese F, Pasta A, Bodini G, Furnari M, Zentilin P, Giannini EG, et al. Applying Lyon consensus criteria in the work-up of patients with extra-oesophageal symptoms – A multicentre retrospective study. Aliment Pharmacol Ther. 2024;59:1134–1143. https://doi.org/10.1111/apt.17934

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