- Email: [email protected]
multichannel impedance monitoring in patients with laryngo-pharyngeal reflux symptoms – Prediction of therapy response in long-term follow-up
Arab Journal of Gastroenterology xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Original Article
pH/multichannel impedance monitoring in patients with laryngo-pharyngeal reflux symptoms – Prediction of therapy response in long-term follow-up Simon Nennstiel a, Mack Andrea a, Mohamed Abdelhafez a, Bernhard Haller b, Roland M. Schmid a, Monther Bajbouj a, Valentin Becker a,⇑ a b
II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Straße 22, 81675 München, Germany Institut für Medizinische Statistik und Epidemiologie, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Straße 22, 81675 München, Germany
a r t i c l e
i n f o
Article history: Received 3 August 2016 Accepted 25 August 2016 Available online xxxx Keywords: Laryngopharyngeal reflux pH/multichannel impedance (MII) monitoring PPI GERD Atypical manifestations of GERD
a b s t r a c t Background and study aim: Optimal therapy concepts in patients with laryngo-pharyngeal reflux (LPR) are still under discussion. Aim of this study was to evaluate long term symptom relief according to results in combined pH/multichannel impedance (MII) monitoring to predict therapy response and symptom relief during long term follow-up. Patients and methods: In patients with predominant LPR symptoms, pH/MII monitoring and subsequent proton pump inhibitor (PPI) therapy were evaluated retrospectively after a minimum follow-up period of 36 months. Patients were asked to complete symptom based questionnaires. Results: 45 patients were evaluated and classified according to results of pH/MII. Twenty one patients showed a pathological finding in pH/MII. These patients reported significantly higher LPR-symptom intensity scores and a significantly higher LPR symptom-induced impairment of everyday life scores compared to patients with normal pH/MII monitoring at baseline and at follow-up. PPI associated symptom relief was significantly higher in patients with pathologic pH/MII monitoring (p = 0.003). Conclusion: In conclusion, combined pH/MII monitoring can reliably predict therapy response to PPIs in LPR patients. With negative results, PPI therapy should be avoided. This approach should be assessed in future prospective clinical trials. Ó 2016 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Introduction Incidence of laryngopharyngeal reflux (LPR) has strongly increased over the last years [1,2]. According to the Montreal classification, the atypical manifestations of gastro-oesophageal reflux disease (GERD) comprise chronic cough, hoarseness, asthma and laryngitis [3–5]. It is postulated, that LPR symptoms are a result of laryngeal or pharyngeal alterations after exposure to acid gastric refluxate [2]. Combined multichannel impedance (pH/MII) and 2-channel pH-monitoring are discussed to be the most reliable tools to diagnose LPR [6,7]. Optimal therapy concepts are still under discussion. Whilst the American Gastroenterological Association does not recommend proton pump inhibitor (PPI) therapy in the absence of concomitant typical gastro-oesophageal reflux disease (GERD) symptoms, the American Academy of OtolaryngologyHead and Neck Surgery recommends in a position statement high ⇑ Corresponding author.
dose acid suppression twice daily for prolonged periods of time [8]. Irrespective of the therapy concept, some symptom-based studies indicate a symptom relief during two year follow-up [9]; in other studies a substantial group of patients did not adequately respond to acid suppression [10]. Despite marginal therapeutic effects and potential side effects, long term PPI therapy is generally applied and generates a substantial economic burden [11,12]. So far, it is unclear which group of patients might benefit from PPI therapy. To overcome this dilemma, a diagnostic tool to guide medical therapy and predict long term therapy results in patients with LPR would be worthwhile. Aim of this study was to evaluate long term symptom relief in patients with predominant atypical reflux symptoms according to results in pH/MII monitoring to predict therapy response and symptom relief during long term follow-up. This is of high clinical interest since the number of patients with LPR and the PPI use in these patients is rising dramatically, thus, the economic burden regarding LPR therapy is constantly increasing.
E-mail address: [email protected] (V. Becker). http://dx.doi.org/10.1016/j.ajg.2016.08.007 1687-1979/Ó 2016 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Nennstiel S et al. pH/multichannel impedance monitoring in patients with laryngo-pharyngeal reflux symptoms – Prediction of therapy response in long-term follow-up. Arab J Gastroenterol (2016), http://dx.doi.org/10.1016/j.ajg.2016.08.007
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S. Nennstiel et al. / Arab Journal of Gastroenterology xxx (2016) xxx–xxx
Patients and methods In this retrospective study, consecutive patients with predominant LPR symptoms defined by the Montreal definition and classification were included. [3]. Patients were identified using the hospital pH/MII-monitoring database in the specified time period from May 1st 2012 to May, 31st 2013. Inclusion criteria were performed pH/MII monitoring and subsequent acid suppression therapy (high dose PPI use for at least 3 months), eligibility for reevaluation after a minimum follow-up period of 36 months and oesophagogastroduodenoscopy (OGD) within the last 3 months prior to pH/MII monitoring to exclude malignancy or relevant pathology. Exclusion criteria were gastric or oesophageal surgery or motility disorders of the upper gastrointestinal tract. The study was approved by the local Ethics Committee of the Technische Universität München (protocol-No. 285/16S). Before initial pH/MII, all patients were asked to complete a symptom-based questionnaire regarding the intensity of atypical reflux symptoms and symptom induced impairment of everyday life, each with a 10-point likert-scale. The same questionnaire was applied in a follow-up appointment at least 36 months after initial pH/MII measurement. At time of follow-up appointment, patients were additionally asked about improvement of symptoms before and after PPI-therapy on a 10-point likert-scale. Symptom relief (after the follow-up period and after PPI-therapy) was defined as symptom reduction of at least 3 points on the corresponding 10 point likert-scales. Questionnaire and likert-scale were adopted from previous trials [13,14]. Combined pH/MII monitoring was performed as described previously [13]. The combined multichannel impedance and single pH channel monitoring catheter (Tecnomatix, Sandhill Scientific, United States) was placed according to manufacturer’s recommendation at predefined spots with the pH probe 5 centimetres above the manometrically defined upper margin of the lower oesophageal sphincter. Measurement was performed for at least 22 h and data were stored and analysed with the respective device (BioView, Sandhill Scientific, United States). All pH/MII measurements were performed ‘‘off” PPI therapy. PH monitoring was defined as pathologic in case the pH value was below 4 for more than 4% of the complete measuring period. Impedance monitoring was considered pathological when more than 73 fluid and/or mixed reflux episodes occurred in the oesophagus. PPI therapy was defined as high dose use of pantoprazole twice a day (80 mg per day) or equal for at least three months. In our department, PPI therapy recommendation was according to results of pH/MII monitoring. In patients with pathological results, we recommended high dose therapy for three months. Thereafter, dose reduction according to symptoms was suggested. In patients with regular pH/MII results, no PPI therapy was recommended. In the analysed study population, PPI therapy was initiated/continued by other specialists like ENT doctors or the patients themselves.
statistical tests were performed two-sided on a level of significance of 5%. Results A total of 45 patients (male: 58%, female: 42%, mean age: 58.6 ± 15.3 years) with predominant LPR-symptoms and a history of pH/MII monitoring with subsequent PPI-treatment, completed the questionnaire after a median of 39 months (range 37–42 months) following the pH/MII-monitoring. In these patients, no technical failures or medical complications occurred during the pH/MII- procedures. For further analysis, patients were divided into two groups. Patients with pathological results in pH and/or impedance monitoring were allocated to group one (n = 21), patients with regular results in pH and/or impedance monitoring to group two (n = 24). The groups showed no differences regarding the patients’ age (mean age group one: 58 ± 13.3 years; mean age group two: 59 ± 17.1 years; p = 0.554) or gender (male gender group one: 58%; male gender group two: 57%; p = 1.0). The duration of PPI therapy was comparable in both groups with 23.2 months (4–41 months) in group one and 27.7 months (3–41 months) in group two (p = 0.497). After the follow-up period, 60% of patients reported a relevant total symptom relief. There was no statistically significant difference regarding this symptom relief between both groups (group one: 66.7%; group two: 54.2%; p = 0.543). Initial symptom intensity score was significantly higher in group one compared to group two (group one: median 7 points; group two: median 5 points; p < 0.001). After the follow-up period, the symptom intensity score was still significantly higher in group one compared to group two (group 1: median 4; group 2 median 3 point; p = 0.004) (Fig. 1). PPI associated symptom relief was reported in 66.7% of patients in group one and in 16.7% in group two (p < 0.001). Symptom intensity score before PPI-treatment was statistically significantly higher in group one (group one: median 7 points; group two median 5 points; p < 0.001), however after PPI course, symptom intensity score did not significantly differ between both groups (group 1: median 5 points; group 2 median 4 points; p = 0.279) (Fig. 2). There was a statistically significant higher reduction in symptom scores after PPI therapy in group one compared to group two (group one: median 2 points; group two: median 1 point; p = 0.003). Initial symptom-induced impairment of everyday life score was statistically significantly more intense in group one (group one:
Statistical analysis To summarise distributions of quantitative variables with skewed distributions (length of follow-up, length of PPI therapy) and distributions of ordinal symptom scores, medians are presented. Minimum and maximum of the observed values are shown, if reasonable. For patient age mean and standard deviation are presented. Distributions of quantitative or ordinal outcomes were compared between the groups with the Mann–Whitney U test. For qualitative outcomes absolute and relative frequencies are given. Fisher’s exact test was conducted in order to compare frequency distributions between the groups of interest. All
Fig. 1. Overall LPR-symptom intensity score initially and after follow-up in patients with normal and pathologic pH/MII-monitoring.
Please cite this article in press as: Nennstiel S et al. pH/multichannel impedance monitoring in patients with laryngo-pharyngeal reflux symptoms – Prediction of therapy response in long-term follow-up. Arab J Gastroenterol (2016), http://dx.doi.org/10.1016/j.ajg.2016.08.007
S. Nennstiel et al. / Arab Journal of Gastroenterology xxx (2016) xxx–xxx
Fig. 2. LPR-symptom score before and after PPI-treatment in patients with initially normal and pathologic pH/MII-monitoring.
Fig. 3. Impairment of everyday life score initially and after follow-up in patients with normal and pathologic pH/MII-monitoring.
median 6 points; group two: median 4.5 points; p < 0.001). At follow-up, symptom-induced impairment of everyday life score was still significantly higher in group one compared to group two (group one: median 4 points; group two: median 3 points; p = 0.008) (Fig. 3). In both groups, some patients reported occasional concomitant GERD symptoms (group one: 12/21 patients (57%), group two: 10/24 patients (41.6%); p = 0.376). Therapy response rate was 83.3% in group one (10/12 patients) and 70% (7/10 patients) in group two (p = 0.624). Discussion In everyday clinical practice we see the problem of an increasing number of patients with LPR symptoms refractory to PPI therapy. High-dose PPI therapy is usually initiated by ear-nose-throat (ENT) specialists and patients often continue this therapy regime for years – frequently with marginal clinical effects only. Presumably, in a relevant number of patients there is no urgent need for PPI therapy. However, there is a group of LPR patients who adequately respond to PPI. With respect to potential side effects and enormous general economic burden, PPIs use should be restricted [10,11]. The decision whether to start or continue a PPI-treatment or stop it is still challenging, because it is unclear which group of
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patients will respond to PPIs and in addition different medical societies give contrary advices. Taking the potential pathomechanism of laryngopharyngeal reflux symptoms into consideration, the PPI-therapy ‘‘question” could possibly be answered with the results of the presented study. LPR patients might be divided into two subgroups; separating patients with objective gastrooesophageal reflux from patients lacking this objective diagnosis. This subdivision was applied in the present trial using pH/MII monitoring. In the group with pathological pH/MII monitoring, symptoms of LPR might probably be caused by direct affection of the pharyngeal and laryngeal mucosa by gastric content as a consequence of gastro-oesophageal reflux disease (GERD). In this group of patients, the symptom intensity score and symptom-induced impairment of everyday life score were significantly higher at baseline as well as at follow-up compared to the group with normal results in pH/MII. Of particular importance is the fact that significantly more patients with pathological pH/MII monitoring responded to PPI therapy. There was also a statistically significant higher PPI associated relief of symptoms compared to the group of patients with normal pH/MII monitoring. So in LPR patients with proven gastrooesophageal reflux, PPI therapy seems to be a promising therapeutic concept and high dose PPIs are recommended. Interestingly, despite significant PPI associated symptom relief, still half of the patients with pathological results in pH/MII monitoring report LPR related impairment of everyday life at follow-up. In the group with normal pH/MII-monitoring, symptoms might be caused by other mechanisms: The Altman group reported expression of laryngeal H+/K+-ATPase proton-pumps in the laryngeal epithelium which might have an effect on laryngeal pH levels [15]. Our study group could not confirm higher numbers of H+/K+-ATPase proton-pumps or a relevant pH drop in a small group [16], however, laryngeal H+K+-ATPase proton pumps might also be blocked by PPIs. Other study groups discuss the ‘‘irritable larynx” which might be caused by alternations in the laryngeal sensitivity by neuropathy of the superior and recurrent laryngeal nerves [17]. This might explain previous results from our study group which showed that patients with LPR symptoms do not necessarily have any correlation between gastro-oesophageal reflux episodes and symptoms [18]. In summary, the reason and aetiology of LPR symptoms in the subgroup of patients with normal pH/MII-monitoring remain unclear and might not be directly associated with gastric reflux, which could explain PPI non-response. In the present trial, PPI therapy in these patients did not result in a significant therapeutic effect. Interestingly, symptom intensity was significantly lower compared to patients with pathological results in pH/MII and there was a relevant relief of symptom intensity in 54% of these patients during follow-up despite PPI non-response. In patients with normal pH/MII-monitoring we support following the American Gastroenterological Association recommendations and avoid PPI therapy. We suggest a close collaboration between gastroenterology, otolaryngology and if necessary pneumology specialists. In the present study, we only studied patients with high dose PPI use for at least 3 months after pH/MII monitoring to evaluate the PPI effect. We recommend PPI therapy only in patients with pathological results in pH/MII, but in concordance with previous data and as seen in our outpatient department, a relevant number of patients insisted on continuing the PPI therapy despite contrary medical recommendations [11]. Continuation of therapy was of great benefit for our trial, because PPI response in pH/MII negative patients could be evaluated. PPI use in the group of patients with regular results in pH/MII was even longer compared to the group with pathological results in pH/MII (not statistically significant) – despite reported non-response to PPIs. High dose PPI therapy for more than three months was not recommended in any patient.
Please cite this article in press as: Nennstiel S et al. pH/multichannel impedance monitoring in patients with laryngo-pharyngeal reflux symptoms – Prediction of therapy response in long-term follow-up. Arab J Gastroenterol (2016), http://dx.doi.org/10.1016/j.ajg.2016.08.007
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However, long term use of PPIs often represents a normal course in patients with LPR. In both groups about half of the patients reported occasional concomitant typical reflux symptoms. Therapy response rate was comparable in both groups and corresponds with previous reported response rates for typical reflux symptoms [19]. Patients with concomitant reflux symptoms in the group with negative results in pH/MII reported only infrequent reflux symptoms of minor intensity. There are limitations to this study that have to be mentioned. First of all, data were collected retrospectively in only one single centre. Second, only patients with previously performed pH/MII monitoring were included, which might have caused a selection bias. Furthermore, PPI therapy was only standardised in the first three months. Thereafter, PPI intake was not standardised with regard to duration. Moreover, symptom relief was only assessed as a symptomatic parameter. Most patients do not tolerate repeated pH/MII monitoring, so no objective data at follow-up could be analysed. Other factors potentially influencing LPR symptoms like concurrent medications or lifestyle modifications could also not be addressed in the present study because of its retrospective nature. However, patients with relevant alterations like gastric surgery were excluded. Still, we believe that the presented patients are a representative group of LPR patients seen in daily clinical practice. In conclusion, combined pH/MII monitoring can predict therapy response to PPIs in patients with LPR symptoms. In negative results, PPI therapy should be avoided and interdisciplinary therapy management is recommended. This approach to patients with predominant LPR-symptoms should be assessed in future prospective clinical trials. Financial disclosures None. Conflicts of interest The authors declared that there was no conflict of interest. References [1] Hicks DM, Ours TM, Abelson TI. The prevalence of hypopharynx findings associated with gastroesophageal reflux in normal volunteers. J Voice 2002;16:564.
[2] Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope 1991;101(4 Pt 2 Suppl. 53):7–78. [3] Vakil N, van Zanten SV, Kahrilas P, et al. Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:1900–20. [4] Ford CN. Evaluation and management of laryngopharyngeal reflux. JAMA 2005;294:1534–40. [5] Rohof WO, Hirsch DP, Boeckxstaens GE. Pathophysiology and management of gastroesophageal reflux disease. Minerva Gastroenterol Dietol 2009;55:289–300. [6] Bredenoord AJ. Impedance-pH monitoring: new standard for measuring gastro-oesophageal reflux. Neurogastroenterol Motil 2008;20:434–9. [7] Bajbouj M, Becker V, Neuber M, et al. Combined pH-metry/impedance monitoring increases the diagnostic yield in patients with atypical gastroesophageal reflux symptoms. Digestion 2007;76:223–8. [8] Kahrilas PJ, Shaheen NJ, Vaezi MF. American gastroenterological association institute; clinical practice and quality management committee. American gastroenterological association institute technical review on the management of gastroesophageal reflux disease. Gastroenterology 2008;135:1392–413. [9] Jaspersen D, Labenz J, Willich SN, et al. Long-term clinical course of extraoesophageal manifestations in patients with gastro-oesophageal reflux disease. A prospective follow-up analysis based on the ProGERD study. Dig Liver Dis 2006;38:233–8. [10] Steward DL, Wilson KM, Kelly DH, et al. Proton pump inhibitor therapy for chronic laryngo-pharyngitis: a randomized placebo-control trial. Otolaryngol Head Neck Surg 2004;131:342–50. [11] Francis DO, Rymer JA, Slaughter JC, et al. High economic burden of caring for patients with suspected extraesophageal reflux. Am J Gastroenterol 2013;108:905–11. [12] Moghimi-Dehkordi B, Vahedi M, Khoshkrood Mansoori B, Kasaeian A, Safaee A, Habibi M, et al. Economic burden of gastro-oesophageal reflux disease and dyspepsia: a community-based study. Arab J Gastroenterol 2011;12(2):86–9. Epub 2011 May 6 PMID: 21684479. [13] Becker V, Grotz S, Schlag C, et al. Positive predictors for gastroesophageal reflux disease and the therapeutic response to proton-pump inhibitors. World J Gastroenterol 2014;20:4017–24. [14] Vaezi MF, Richter JE, Stasney CR, et al. Treatment of chronic posterior laryngitis with esomeprazole. Laryngoscope 2006;20:116–254. [15] Altman KW, Haines 3rd GK, Hammer ND, et al. The H+/K+-ATPase (proton) pump is expressed in human laryngeal submucosal glands. Laryngoscope 2003;113:1927. [16] Becker V, Drabner R, Graf S, et al. New aspects in the pathomechanism and diagnosis of the laryngopharyngeal reflux-clinical impact of laryngeal proton pumps and pharyngeal pH metry in extraesophageal gastroesophageal reflux disease. World J Gastroenterol 2015;21:982–7. [17] Pacheco A, Cobeta I. Refractory chronic cough, or the need to focus on the relationship between the larynx and the esophagus. Cough 2013;9:10. [18] Becker V, Graf S, Schlag C, et al. First agreement analysis and day-to-day comparison of pharyngeal pH monitoring with pH/impedance monitoring in patients with suspected laryngopharyngeal reflux. J Gastrointest Surg 2012;16:1096–101. [19] Hunt R. Acid suppression for reflux disease: ‘‘off-the-peg” or a tailored approach? Clin Gastroenterol Hepatol 2012;10(3):210–3. Epub 2011 Dec 2.
Please cite this article in press as: Nennstiel S et al. pH/multichannel impedance monitoring in patients with laryngo-pharyngeal reflux symptoms – Prediction of therapy response in long-term follow-up. Arab J Gastroenterol (2016), http://dx.doi.org/10.1016/j.ajg.2016.08.007
Contents lists available at ScienceDirect
Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Original Article
pH/multichannel impedance monitoring in patients with laryngo-pharyngeal reflux symptoms – Prediction of therapy response in long-term follow-up Simon Nennstiel a, Mack Andrea a, Mohamed Abdelhafez a, Bernhard Haller b, Roland M. Schmid a, Monther Bajbouj a, Valentin Becker a,⇑ a b
II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Straße 22, 81675 München, Germany Institut für Medizinische Statistik und Epidemiologie, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Straße 22, 81675 München, Germany
a r t i c l e
i n f o
Article history: Received 3 August 2016 Accepted 25 August 2016 Available online xxxx Keywords: Laryngopharyngeal reflux pH/multichannel impedance (MII) monitoring PPI GERD Atypical manifestations of GERD
a b s t r a c t Background and study aim: Optimal therapy concepts in patients with laryngo-pharyngeal reflux (LPR) are still under discussion. Aim of this study was to evaluate long term symptom relief according to results in combined pH/multichannel impedance (MII) monitoring to predict therapy response and symptom relief during long term follow-up. Patients and methods: In patients with predominant LPR symptoms, pH/MII monitoring and subsequent proton pump inhibitor (PPI) therapy were evaluated retrospectively after a minimum follow-up period of 36 months. Patients were asked to complete symptom based questionnaires. Results: 45 patients were evaluated and classified according to results of pH/MII. Twenty one patients showed a pathological finding in pH/MII. These patients reported significantly higher LPR-symptom intensity scores and a significantly higher LPR symptom-induced impairment of everyday life scores compared to patients with normal pH/MII monitoring at baseline and at follow-up. PPI associated symptom relief was significantly higher in patients with pathologic pH/MII monitoring (p = 0.003). Conclusion: In conclusion, combined pH/MII monitoring can reliably predict therapy response to PPIs in LPR patients. With negative results, PPI therapy should be avoided. This approach should be assessed in future prospective clinical trials. Ó 2016 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Introduction Incidence of laryngopharyngeal reflux (LPR) has strongly increased over the last years [1,2]. According to the Montreal classification, the atypical manifestations of gastro-oesophageal reflux disease (GERD) comprise chronic cough, hoarseness, asthma and laryngitis [3–5]. It is postulated, that LPR symptoms are a result of laryngeal or pharyngeal alterations after exposure to acid gastric refluxate [2]. Combined multichannel impedance (pH/MII) and 2-channel pH-monitoring are discussed to be the most reliable tools to diagnose LPR [6,7]. Optimal therapy concepts are still under discussion. Whilst the American Gastroenterological Association does not recommend proton pump inhibitor (PPI) therapy in the absence of concomitant typical gastro-oesophageal reflux disease (GERD) symptoms, the American Academy of OtolaryngologyHead and Neck Surgery recommends in a position statement high ⇑ Corresponding author.
dose acid suppression twice daily for prolonged periods of time [8]. Irrespective of the therapy concept, some symptom-based studies indicate a symptom relief during two year follow-up [9]; in other studies a substantial group of patients did not adequately respond to acid suppression [10]. Despite marginal therapeutic effects and potential side effects, long term PPI therapy is generally applied and generates a substantial economic burden [11,12]. So far, it is unclear which group of patients might benefit from PPI therapy. To overcome this dilemma, a diagnostic tool to guide medical therapy and predict long term therapy results in patients with LPR would be worthwhile. Aim of this study was to evaluate long term symptom relief in patients with predominant atypical reflux symptoms according to results in pH/MII monitoring to predict therapy response and symptom relief during long term follow-up. This is of high clinical interest since the number of patients with LPR and the PPI use in these patients is rising dramatically, thus, the economic burden regarding LPR therapy is constantly increasing.
E-mail address: [email protected] (V. Becker). http://dx.doi.org/10.1016/j.ajg.2016.08.007 1687-1979/Ó 2016 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Nennstiel S et al. pH/multichannel impedance monitoring in patients with laryngo-pharyngeal reflux symptoms – Prediction of therapy response in long-term follow-up. Arab J Gastroenterol (2016), http://dx.doi.org/10.1016/j.ajg.2016.08.007
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S. Nennstiel et al. / Arab Journal of Gastroenterology xxx (2016) xxx–xxx
Patients and methods In this retrospective study, consecutive patients with predominant LPR symptoms defined by the Montreal definition and classification were included. [3]. Patients were identified using the hospital pH/MII-monitoring database in the specified time period from May 1st 2012 to May, 31st 2013. Inclusion criteria were performed pH/MII monitoring and subsequent acid suppression therapy (high dose PPI use for at least 3 months), eligibility for reevaluation after a minimum follow-up period of 36 months and oesophagogastroduodenoscopy (OGD) within the last 3 months prior to pH/MII monitoring to exclude malignancy or relevant pathology. Exclusion criteria were gastric or oesophageal surgery or motility disorders of the upper gastrointestinal tract. The study was approved by the local Ethics Committee of the Technische Universität München (protocol-No. 285/16S). Before initial pH/MII, all patients were asked to complete a symptom-based questionnaire regarding the intensity of atypical reflux symptoms and symptom induced impairment of everyday life, each with a 10-point likert-scale. The same questionnaire was applied in a follow-up appointment at least 36 months after initial pH/MII measurement. At time of follow-up appointment, patients were additionally asked about improvement of symptoms before and after PPI-therapy on a 10-point likert-scale. Symptom relief (after the follow-up period and after PPI-therapy) was defined as symptom reduction of at least 3 points on the corresponding 10 point likert-scales. Questionnaire and likert-scale were adopted from previous trials [13,14]. Combined pH/MII monitoring was performed as described previously [13]. The combined multichannel impedance and single pH channel monitoring catheter (Tecnomatix, Sandhill Scientific, United States) was placed according to manufacturer’s recommendation at predefined spots with the pH probe 5 centimetres above the manometrically defined upper margin of the lower oesophageal sphincter. Measurement was performed for at least 22 h and data were stored and analysed with the respective device (BioView, Sandhill Scientific, United States). All pH/MII measurements were performed ‘‘off” PPI therapy. PH monitoring was defined as pathologic in case the pH value was below 4 for more than 4% of the complete measuring period. Impedance monitoring was considered pathological when more than 73 fluid and/or mixed reflux episodes occurred in the oesophagus. PPI therapy was defined as high dose use of pantoprazole twice a day (80 mg per day) or equal for at least three months. In our department, PPI therapy recommendation was according to results of pH/MII monitoring. In patients with pathological results, we recommended high dose therapy for three months. Thereafter, dose reduction according to symptoms was suggested. In patients with regular pH/MII results, no PPI therapy was recommended. In the analysed study population, PPI therapy was initiated/continued by other specialists like ENT doctors or the patients themselves.
statistical tests were performed two-sided on a level of significance of 5%. Results A total of 45 patients (male: 58%, female: 42%, mean age: 58.6 ± 15.3 years) with predominant LPR-symptoms and a history of pH/MII monitoring with subsequent PPI-treatment, completed the questionnaire after a median of 39 months (range 37–42 months) following the pH/MII-monitoring. In these patients, no technical failures or medical complications occurred during the pH/MII- procedures. For further analysis, patients were divided into two groups. Patients with pathological results in pH and/or impedance monitoring were allocated to group one (n = 21), patients with regular results in pH and/or impedance monitoring to group two (n = 24). The groups showed no differences regarding the patients’ age (mean age group one: 58 ± 13.3 years; mean age group two: 59 ± 17.1 years; p = 0.554) or gender (male gender group one: 58%; male gender group two: 57%; p = 1.0). The duration of PPI therapy was comparable in both groups with 23.2 months (4–41 months) in group one and 27.7 months (3–41 months) in group two (p = 0.497). After the follow-up period, 60% of patients reported a relevant total symptom relief. There was no statistically significant difference regarding this symptom relief between both groups (group one: 66.7%; group two: 54.2%; p = 0.543). Initial symptom intensity score was significantly higher in group one compared to group two (group one: median 7 points; group two: median 5 points; p < 0.001). After the follow-up period, the symptom intensity score was still significantly higher in group one compared to group two (group 1: median 4; group 2 median 3 point; p = 0.004) (Fig. 1). PPI associated symptom relief was reported in 66.7% of patients in group one and in 16.7% in group two (p < 0.001). Symptom intensity score before PPI-treatment was statistically significantly higher in group one (group one: median 7 points; group two median 5 points; p < 0.001), however after PPI course, symptom intensity score did not significantly differ between both groups (group 1: median 5 points; group 2 median 4 points; p = 0.279) (Fig. 2). There was a statistically significant higher reduction in symptom scores after PPI therapy in group one compared to group two (group one: median 2 points; group two: median 1 point; p = 0.003). Initial symptom-induced impairment of everyday life score was statistically significantly more intense in group one (group one:
Statistical analysis To summarise distributions of quantitative variables with skewed distributions (length of follow-up, length of PPI therapy) and distributions of ordinal symptom scores, medians are presented. Minimum and maximum of the observed values are shown, if reasonable. For patient age mean and standard deviation are presented. Distributions of quantitative or ordinal outcomes were compared between the groups with the Mann–Whitney U test. For qualitative outcomes absolute and relative frequencies are given. Fisher’s exact test was conducted in order to compare frequency distributions between the groups of interest. All
Fig. 1. Overall LPR-symptom intensity score initially and after follow-up in patients with normal and pathologic pH/MII-monitoring.
Please cite this article in press as: Nennstiel S et al. pH/multichannel impedance monitoring in patients with laryngo-pharyngeal reflux symptoms – Prediction of therapy response in long-term follow-up. Arab J Gastroenterol (2016), http://dx.doi.org/10.1016/j.ajg.2016.08.007
S. Nennstiel et al. / Arab Journal of Gastroenterology xxx (2016) xxx–xxx
Fig. 2. LPR-symptom score before and after PPI-treatment in patients with initially normal and pathologic pH/MII-monitoring.
Fig. 3. Impairment of everyday life score initially and after follow-up in patients with normal and pathologic pH/MII-monitoring.
median 6 points; group two: median 4.5 points; p < 0.001). At follow-up, symptom-induced impairment of everyday life score was still significantly higher in group one compared to group two (group one: median 4 points; group two: median 3 points; p = 0.008) (Fig. 3). In both groups, some patients reported occasional concomitant GERD symptoms (group one: 12/21 patients (57%), group two: 10/24 patients (41.6%); p = 0.376). Therapy response rate was 83.3% in group one (10/12 patients) and 70% (7/10 patients) in group two (p = 0.624). Discussion In everyday clinical practice we see the problem of an increasing number of patients with LPR symptoms refractory to PPI therapy. High-dose PPI therapy is usually initiated by ear-nose-throat (ENT) specialists and patients often continue this therapy regime for years – frequently with marginal clinical effects only. Presumably, in a relevant number of patients there is no urgent need for PPI therapy. However, there is a group of LPR patients who adequately respond to PPI. With respect to potential side effects and enormous general economic burden, PPIs use should be restricted [10,11]. The decision whether to start or continue a PPI-treatment or stop it is still challenging, because it is unclear which group of
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patients will respond to PPIs and in addition different medical societies give contrary advices. Taking the potential pathomechanism of laryngopharyngeal reflux symptoms into consideration, the PPI-therapy ‘‘question” could possibly be answered with the results of the presented study. LPR patients might be divided into two subgroups; separating patients with objective gastrooesophageal reflux from patients lacking this objective diagnosis. This subdivision was applied in the present trial using pH/MII monitoring. In the group with pathological pH/MII monitoring, symptoms of LPR might probably be caused by direct affection of the pharyngeal and laryngeal mucosa by gastric content as a consequence of gastro-oesophageal reflux disease (GERD). In this group of patients, the symptom intensity score and symptom-induced impairment of everyday life score were significantly higher at baseline as well as at follow-up compared to the group with normal results in pH/MII. Of particular importance is the fact that significantly more patients with pathological pH/MII monitoring responded to PPI therapy. There was also a statistically significant higher PPI associated relief of symptoms compared to the group of patients with normal pH/MII monitoring. So in LPR patients with proven gastrooesophageal reflux, PPI therapy seems to be a promising therapeutic concept and high dose PPIs are recommended. Interestingly, despite significant PPI associated symptom relief, still half of the patients with pathological results in pH/MII monitoring report LPR related impairment of everyday life at follow-up. In the group with normal pH/MII-monitoring, symptoms might be caused by other mechanisms: The Altman group reported expression of laryngeal H+/K+-ATPase proton-pumps in the laryngeal epithelium which might have an effect on laryngeal pH levels [15]. Our study group could not confirm higher numbers of H+/K+-ATPase proton-pumps or a relevant pH drop in a small group [16], however, laryngeal H+K+-ATPase proton pumps might also be blocked by PPIs. Other study groups discuss the ‘‘irritable larynx” which might be caused by alternations in the laryngeal sensitivity by neuropathy of the superior and recurrent laryngeal nerves [17]. This might explain previous results from our study group which showed that patients with LPR symptoms do not necessarily have any correlation between gastro-oesophageal reflux episodes and symptoms [18]. In summary, the reason and aetiology of LPR symptoms in the subgroup of patients with normal pH/MII-monitoring remain unclear and might not be directly associated with gastric reflux, which could explain PPI non-response. In the present trial, PPI therapy in these patients did not result in a significant therapeutic effect. Interestingly, symptom intensity was significantly lower compared to patients with pathological results in pH/MII and there was a relevant relief of symptom intensity in 54% of these patients during follow-up despite PPI non-response. In patients with normal pH/MII-monitoring we support following the American Gastroenterological Association recommendations and avoid PPI therapy. We suggest a close collaboration between gastroenterology, otolaryngology and if necessary pneumology specialists. In the present study, we only studied patients with high dose PPI use for at least 3 months after pH/MII monitoring to evaluate the PPI effect. We recommend PPI therapy only in patients with pathological results in pH/MII, but in concordance with previous data and as seen in our outpatient department, a relevant number of patients insisted on continuing the PPI therapy despite contrary medical recommendations [11]. Continuation of therapy was of great benefit for our trial, because PPI response in pH/MII negative patients could be evaluated. PPI use in the group of patients with regular results in pH/MII was even longer compared to the group with pathological results in pH/MII (not statistically significant) – despite reported non-response to PPIs. High dose PPI therapy for more than three months was not recommended in any patient.
Please cite this article in press as: Nennstiel S et al. pH/multichannel impedance monitoring in patients with laryngo-pharyngeal reflux symptoms – Prediction of therapy response in long-term follow-up. Arab J Gastroenterol (2016), http://dx.doi.org/10.1016/j.ajg.2016.08.007
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S. Nennstiel et al. / Arab Journal of Gastroenterology xxx (2016) xxx–xxx
However, long term use of PPIs often represents a normal course in patients with LPR. In both groups about half of the patients reported occasional concomitant typical reflux symptoms. Therapy response rate was comparable in both groups and corresponds with previous reported response rates for typical reflux symptoms [19]. Patients with concomitant reflux symptoms in the group with negative results in pH/MII reported only infrequent reflux symptoms of minor intensity. There are limitations to this study that have to be mentioned. First of all, data were collected retrospectively in only one single centre. Second, only patients with previously performed pH/MII monitoring were included, which might have caused a selection bias. Furthermore, PPI therapy was only standardised in the first three months. Thereafter, PPI intake was not standardised with regard to duration. Moreover, symptom relief was only assessed as a symptomatic parameter. Most patients do not tolerate repeated pH/MII monitoring, so no objective data at follow-up could be analysed. Other factors potentially influencing LPR symptoms like concurrent medications or lifestyle modifications could also not be addressed in the present study because of its retrospective nature. However, patients with relevant alterations like gastric surgery were excluded. Still, we believe that the presented patients are a representative group of LPR patients seen in daily clinical practice. In conclusion, combined pH/MII monitoring can predict therapy response to PPIs in patients with LPR symptoms. In negative results, PPI therapy should be avoided and interdisciplinary therapy management is recommended. This approach to patients with predominant LPR-symptoms should be assessed in future prospective clinical trials. Financial disclosures None. Conflicts of interest The authors declared that there was no conflict of interest. References [1] Hicks DM, Ours TM, Abelson TI. The prevalence of hypopharynx findings associated with gastroesophageal reflux in normal volunteers. J Voice 2002;16:564.
[2] Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope 1991;101(4 Pt 2 Suppl. 53):7–78. [3] Vakil N, van Zanten SV, Kahrilas P, et al. Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:1900–20. [4] Ford CN. Evaluation and management of laryngopharyngeal reflux. JAMA 2005;294:1534–40. [5] Rohof WO, Hirsch DP, Boeckxstaens GE. Pathophysiology and management of gastroesophageal reflux disease. Minerva Gastroenterol Dietol 2009;55:289–300. [6] Bredenoord AJ. Impedance-pH monitoring: new standard for measuring gastro-oesophageal reflux. Neurogastroenterol Motil 2008;20:434–9. [7] Bajbouj M, Becker V, Neuber M, et al. Combined pH-metry/impedance monitoring increases the diagnostic yield in patients with atypical gastroesophageal reflux symptoms. Digestion 2007;76:223–8. [8] Kahrilas PJ, Shaheen NJ, Vaezi MF. American gastroenterological association institute; clinical practice and quality management committee. American gastroenterological association institute technical review on the management of gastroesophageal reflux disease. Gastroenterology 2008;135:1392–413. [9] Jaspersen D, Labenz J, Willich SN, et al. Long-term clinical course of extraoesophageal manifestations in patients with gastro-oesophageal reflux disease. A prospective follow-up analysis based on the ProGERD study. Dig Liver Dis 2006;38:233–8. [10] Steward DL, Wilson KM, Kelly DH, et al. Proton pump inhibitor therapy for chronic laryngo-pharyngitis: a randomized placebo-control trial. Otolaryngol Head Neck Surg 2004;131:342–50. [11] Francis DO, Rymer JA, Slaughter JC, et al. High economic burden of caring for patients with suspected extraesophageal reflux. Am J Gastroenterol 2013;108:905–11. [12] Moghimi-Dehkordi B, Vahedi M, Khoshkrood Mansoori B, Kasaeian A, Safaee A, Habibi M, et al. Economic burden of gastro-oesophageal reflux disease and dyspepsia: a community-based study. Arab J Gastroenterol 2011;12(2):86–9. Epub 2011 May 6 PMID: 21684479. [13] Becker V, Grotz S, Schlag C, et al. Positive predictors for gastroesophageal reflux disease and the therapeutic response to proton-pump inhibitors. World J Gastroenterol 2014;20:4017–24. [14] Vaezi MF, Richter JE, Stasney CR, et al. Treatment of chronic posterior laryngitis with esomeprazole. Laryngoscope 2006;20:116–254. [15] Altman KW, Haines 3rd GK, Hammer ND, et al. The H+/K+-ATPase (proton) pump is expressed in human laryngeal submucosal glands. Laryngoscope 2003;113:1927. [16] Becker V, Drabner R, Graf S, et al. New aspects in the pathomechanism and diagnosis of the laryngopharyngeal reflux-clinical impact of laryngeal proton pumps and pharyngeal pH metry in extraesophageal gastroesophageal reflux disease. World J Gastroenterol 2015;21:982–7. [17] Pacheco A, Cobeta I. Refractory chronic cough, or the need to focus on the relationship between the larynx and the esophagus. Cough 2013;9:10. [18] Becker V, Graf S, Schlag C, et al. First agreement analysis and day-to-day comparison of pharyngeal pH monitoring with pH/impedance monitoring in patients with suspected laryngopharyngeal reflux. J Gastrointest Surg 2012;16:1096–101. [19] Hunt R. Acid suppression for reflux disease: ‘‘off-the-peg” or a tailored approach? Clin Gastroenterol Hepatol 2012;10(3):210–3. Epub 2011 Dec 2.
Please cite this article in press as: Nennstiel S et al. pH/multichannel impedance monitoring in patients with laryngo-pharyngeal reflux symptoms – Prediction of therapy response in long-term follow-up. Arab J Gastroenterol (2016), http://dx.doi.org/10.1016/j.ajg.2016.08.007