Abstract
Objective:
Laryngopharyngeal reflux (LPR) is responsible for many otorhinolaryngology manifestations. There is little evidence regarding the LPR impact on olfaction. No other study has investigated the efficacy of proton pump inhibitors (PPIs) on olfaction. We aimed to evaluate the effect of antireflux medication on olfaction and nasal patency in patients with LPR.
Materials and methods:
Thirty patients with LPR were recruited. Nasal symptoms were self-evaluated with NOSE and SNOT-22 surveys, while a taste visual analogue scale (VAS) was used for gustation. Olfaction was evaluated with Sniffin’ Sticks test and nasal patency with anterior rhinomanometry. After 12 weeks of oral PPIs, the procedure was re-applied and clinical outcomes were compared.
Results:
Variables with statistically significant difference included the olfactory threshold (means 1,87/ SD 3,3/ t -3,11/ p 0,004) and the combined threshold-discrimination-identification (TDI) scores of Sniffin’ Sticks test (means -2,61/ SD 5.26/ t -2.75/ p 0.01) and the self-assessment NOSE (p 0.009) and SNOT-22 (0.031) tests. However, no variable concerning nasal patency revealed statistically significant difference before and after treatment in the study group (p 0.677).
Conclusions:
Oral PPIs treatment was associated with better olfactory threshold and TDI scores. These results raise the need for further studies, regarding the effect of antireflux medication on patients suffering from LPR who express nasal symptoms and olfaction disfunction.
Keywords:: gastroesophageal reflux, laryngopharyngeal reflux, nasal congestion and reflux, proton pump inhibitors and olfaction, olfaction disorders and reflux..
Introduction
Laryngopharyngeal reflux (LPR) is called the reflux of gastric contents like gastric acid, pepsin, enzymes from pancreas and bile above the upper esophageal sphincter at the upper respiratory tract, while in gastroesophageal reflux gastric acid is limited to the esophagus. The exposure of the upper respiratory tract to gastric contents results in various otolaryngological manifestations (1, 2), namely chronic cough, laryngitis, hoarseness, globus pharyngeus, halitosis, chronic rhinosinusitis, postnasal drip, otitis media, olfaction and gustation impairment (3, 4). The link between LPR and olfaction has gained an increased research interest among otolaryngologists due to the critical role of smell in people’s overall quality of life. More specifically, olfaction along with trigeminal nerve pathways play a crucial role to the recognition of environmental hazards and contribute to pleasure perception, nutrition, mood and sexuality. The objective of this study is to evaluate the effect of oral antireflux medication (PPIs) on olfac tion and nasal patency in patients diagnosed with LPR. Very few studies investigating the impact of PPIs on nasal blockage/patency have been published until now, while the response of olfaction to pharmacological therapy has not been studied so far. The purpose of the present study is to investigate whether antireflux medication improves nasal patency and/or olfaction in patients with LPR.
Materials and methods
with NOSE and SNOT-22 surveys, while a taste visual analogue scale (VAS) was used for gustation. Olfaction was evaluated with Sniffin’ Sticks test and nasal patency with anterior rhinomanometry. After 12 weeks of oral PPIs, the procedure was re-applied and clinical outcomes were compared. Results: Variables with statistically significant difference included the olfactory threshold (means 1,87/ SD 3,3/ t -3,11/ p 0,004) and the combined threshold-discrimination-identification (TDI) scores of Sniffin’ Sticks test (means -2,61/ SD 5.26/ t -2.75/ p 0.01) and the self-assessment NOSE (p 0.009) and SNOT-22 (0.031) tests. However, no variable concerning nasal patency revealed statistically significant difference before and after treatment in the study group (p 0.677). Conclusions: Oral PPIs treatment was associated with better olfactory threshold and TDI scores. These results raise the need for further studies, regarding the effect of antireflux medication on patients suffering from LPR who express nasal symptoms and olfaction disfunction. Keywords: gastroesophageal reflux, laryngopharyngeal reflux, nasal congestion and reflux, proton pump inhibitors and olfaction, olfaction disorders and reflux.
W e conducted a prospective cohort clinical study at the Department of Otolaryngology of “Georgios Gennimatas” General Hospital of Thessaloniki, Greece, from April 2020 to March 2023. The study protocol, informed consent and detailed intervention procedure were all submitted to the Ethics Committee for approval. Approval was also received from the Scientific Council of “Georgios Gennimatas” General Hospital of Thessaloniki and the Third Regional Health Directorate. Patients with LPR symptoms were included in the study group and healthy individuals with no LPR symptoms were recruited for the control group. Inclusion criteria Laryngopharyngeal reflux was diagnosed using Belafsky criteria, including the Reflux Symptom Index (RSI) and Reflux Finding Signs (RFS) (5, 6). The RSI questionnaire was filled in by the patient and the RFS one by the doctor after endoscopic assessment of the larynx. Regarding RSI, patients were asked to complete a nine-item questionnaire assessing the severity of their symptoms. Each item was rated by a scale from 0 (no complaint) to five (severe symptoms). A score > 13 was indicative for LPR. For RFS, participants underwent laryngoscopy by the same clinician and eight different signs were assessed. The score ranged from 0 (normal) to 26 (worst), with values higher than 7 being considered as indicative for LPR (5, 6). If RFS>7 and RSI>13, we can accept that patients present LPR and are therefore eligible for the study group. For the individuals of the control group, RFS≤7 and RSI≤13 was considered a necessary demand. Exclusion criteria The following exclusion criteria were applied: pediatric patients, acute or chronic rhinosinusitis, severe nasal septum deviation blocking completely one nostril, systemic diseases, neurodegenerative diseases, post-traumatic nasal or head injuries, all of which may cause some nasal dysfunction affecting olfactory function too. The control group included healthy individuals with no reflux symptoms (RFS≤7 and RSI≤13) and without a history of nasal disease. Size effect Since differences between two distinct parameters (smell/nasal congestion) were requested, we chose a large effect size index (d = 0.8), where the predicted sample size per cohort would be N = 26 people, at the level of significance α = 0.05 and power index β = 0.8, according to Cohen (7). With this size index, the probability of a Type I and and Type II error was 5% and 20%, respectively, with a conservative assessment of the significance of the intervention in solving smell problems and nasal congestion (size index 0.5) (7). For the evaluation of olfactory performance, Sniffin’ Sticks test composed of 112 sticks was used to measure the threshold, discrimination and identification of odors. The extended Sniffin’ Sticks test procedure is a tool for the assessment of chemosensory function of the nose and it is based on distribution of smells with pen-like devices. It comprises three subtests of olfactory function: a test for olfactory threshold (n-butanol); a test for odor discrimination (16 pairs of odors, triple forced choice); and a test for odor identification (16 common odors, multiple forced choice among four written proposals). In addition, patients were asked to fill in the NOSE and SNOT-22 questionnaires for self-evaluation of nasal symptoms, and a taste visual analogue scale (VAS) to assess their gustatory ability. Finally, after the 12-week therapy with PPIs (lansoprazole 30 mg or esomeprazole trihydrate 40 mg), complete ENT examination was repeated, along with rhinomanometry, Sniffin’ Sticks and self-evaluation by filling in the questionnaires. Active anterior rhinomanometry Rhinomanometry is a functional dynamic diagnostic tool for the evaluation of nasal resistance during nasal inspiration. It calculates intranasal pressure and airflow volume. Active anterior rhinomanometry is considered the gold standard for the assessment of the objective evaluation of total transnasal airflow resistance (8). In the current study, anterior rhinomanometry, using Rhinomanometer Atmos 300, was applied for the investigation of nasal congestion before and after antireflux therapy in patients with diagnosed LPR. Anterior rhinomanometry was also used to assess nasal patency in the control group. Statistical analysis In our study, statistical analysis of outcomes was performed using IBM Statistical Package for Social Sciences (SPSS) 20 for Windows. The statistical comparison of the measured clinical variants was done 1) between the control group and the first clinical examination of the study group; and 2) between the first clinical examination and the reevaluation of the study group during a 12-week time. For the selection of the appropriate comparison test, the condition of normal distribution of the differences between the two measurements was examined. Paired samples t-test was used for normal distribution and Wilcoxon signed-ranks test for inverse Gaussian distribution. Pearson’s Chi-squared t-test was employed for group comparisons in nominal variables and percentages.
Results
A control group of 30 healthy individuals and a study group of 30 patients with LPR were included in our study. All participants were assessed for their olfaction and nasal patency. Also, they self-assessed their nasal symptoms and taste sensation. The study group repeated the same protocol after a 12-week course of oral medication (Tables 1 and 4 summarise the values of the control and study groups before and after treatment).
Among the 30 subjects of the study group, there were 24 (80%) women with a mean age of 50.5 years [standard deviation (SD) 13.01 years] (age range 25–66 years) and six (20%) men with a mean age of 50.67 years (SD 6.92 years) (age range 40–60 years).
Among the 30 control group participants, there were 24 (80%) women with a mean age of 45.91 years (SD 11.52 years) (age range 22–63 years) and six (20%) men with mean age of 44.33 years (SD 9.61 years) (age range 28–56 years).
Comparison of the study group initial values and control group measurements: Tables 2 and 3 display comparisons between measurements of the control group and pre-treatment measurements of the study group. The appropriate tests for values with normal and non-normal distribution (t-test and Mann-Whitney test) were selected, respectively. The results showed statistically significant differences in all measured variables, except for total nasal resistance (p 0.189).
Comparison of measurements (values) pre- and post-treatment for the study group: We compared the RFS and RSI values for the study group, before and after three-month of antireflux medication. It is shown that mean values for both RFS and RSI after medication were reduced from 11.5 to 4 and from 22.1 to 11.33, respectively.
Pre- and post-treatment values were compared using the t-test for variable pairs, and the result showed statistically significant differences between pre- and post-treatment values (p<0.001) (Tables 4 and 5).
Comparison of nasal patency values: Active anterior rhinomanometry was used to evaluate participants’ nasal patency before and after the three-month treatment with antireflux agents. Values before and after treatment are depicted in Figure 1 (Table 4). The comparison revealed that treatment with PPIs did not affect nasal resistance. The mean total nasal resistance (Rtot) was 182.895 before treatment and 185.760 after treatment. Pre- and post-treatment values were compared using the t-test for variable pairs. Total resistance did not show statistically significant difference (p 0.677) (Table 5).
Comparison of Sniffin’ Sticks test measurements: The Sniffin’ sticks test procedure was used to assess olfaction before and after antireflux treatment. Identification, discrimination, threshold, and TDI values are shown in Figure 2 and Table 4. The identification score was slightly improved from 13.77 to 14.433 (p 0.077) after treatment for LPR, while the discrimination score remained almost unchanged, from 11.60 to 11.66 (p 0.903). The threshold was improved from 6.53 to 8.41 (p 0.004) and TDI score also raised from 31.9 to 34.54 (p 0.01) (Table 5). It is worth mentioning that patients were fulfilling the exclusion criteria, which potentially would affect the olfactory function. Also, they did not suffer any recent respiratory infection, including covid-19.
For comparison of pre- and post-antireflux treatment value, the paired samples t-test procedure was used. Values of threshold and TDI scores before and after antireflux medication showed statistically significant difference (Table 5, p 0.004 and p 0.01, respectively).
Comparison of self-assessment measurements of nasal symptoms and taste: To assess participants’ perception of their nasal symptoms, we asked them to fill in the NOSE and the SNOT-22 questionnaires. Regarding taste, a VAS from 0 to 10 was used, with 0 standing for poor taste and 10 for excellent taste.
The values before and after antireflux therapy are listed in Figure 3. For the comparison of pre- and post-treatment values for the NOSE variable, the t-test for variable pairs was used (means 12.56 / SD 24.5 / t 2.81 / p 0.009). For the comparison of SNOT-22 and taste-VAS values, the Wilcoxon signed-ranks test was used (Table 5). For SNOT-22, the p value was 0.031, which revealed a significant improvement, though p 0.056 for taste VAS showed no statistically significant difference.
In summary, the differences between variable markers RFS (p<0.001) and RSI (p<0.001) were statistically significant, as expected after administration of PPIs, which implied a successful treatment. The variables of Sniffin tests, TH (p 0.004) and TDI (p 0.01), as well as the nasal symptom self-assessment variables NOSE (p 0.009) and SNOT (p 0.031) revealed statistically significant difference. The taste self-assessment variable approached the threshold of statistical significance (p 0.056). There was no statistically significant difference before and after intervention for nasal patency variables.
Discussion
The results of this study indicate that LPR treatment using proton pump inhibitors (PPIs) is effective in reducing the symptoms of LPR, as measured by the reflux symptom index (RSI) and reflux finding score (RFS). These results are consistent with previous studies that have demonstrated the positive impact of PPIs on LPR symptom management. In this study, there was a significant reduction in both the RSI and RFS values after 12 weeks of treatment with PPIs, indicating an improvement in both the subjective symptoms and objective findings associated with LPR.
While nasal patency, as assessed by anterior rhinomanometry, did not show any significant improvement, there was an observable improvement in olfactory function. This finding is consistent with reports suggesting that LPR can impact olfactory function, and that treatment of LPR may lead to improvements in smell perception. In this study, the threshold for olfactory detection improved significantly, along with the total diagnostic indicator (TDI) score. However, the improvement in the identification and discrimination scores was not statistically significant, which may reflect the multifactorial nature of olfactory dysfunction in LPR patients.
It is important to note that while some patients experienced an improvement in taste sensation, this was not statistically significant. This suggests that while PPIs may help improve certain aspects of LPR symptoms, taste disturbances may be less directly affected or may require a longer duration of treatment to see significant improvements. The lack of significant change in taste perception aligns with previous studies that suggest taste dysfunction in LPR may not be entirely reversible through PPI therapy alone.
The improvement in subjective self-assessments, as measured by the NOSE (Nasal Obstruction Symptom Evaluation) and SNOT-22 (Sinus Nasal Outcome Test) questionnaires, also supports the efficacy of PPIs in treating LPR. Although these scales are designed to measure nasal and sinus symptoms, the positive outcomes suggest that PPI treatment may reduce the severity of symptoms such as nasal congestion, post-nasal drip, and throat irritation, which are commonly associated with LPR.
One limitation of this study is the relatively small sample size, which may impact the generalizability of the findings. Furthermore, the use of subjective measures such as the RSI and RFS, while valuable, may be prone to bias, and a more objective assessment of symptoms would strengthen the results. Future studies with larger sample sizes and longer treatment durations are needed to further evaluate the long-term effects of PPIs on LPR symptoms and their impact on olfactory and taste functions.
Although Dagli et al reported a statistically significant difference concerning nasal patency before and after treatment for LPR, our research found no significant difference using anterior rhinomanometry (3). This discrepancy might be explained by the differences in the patient population, the treatment regimen, or the methodology used to assess nasal patency. The lack of significant improvement in nasal patency in our study suggests that while PPIs may effectively alleviate LPR symptoms, they may not significantly affect nasal airflow or resistance as assessed by rhinomanometry.
Conclusion
In conclusion, this study highlights the significant impact of LPR treatment with proton pump inhibitors (PPIs) on reducing symptoms, as evidenced by the improvement in reflux symptom index (RSI) and reflux finding score (RFS). While nasal patency, as measured by anterior rhinomanometry, did not show a significant improvement, olfactory function and taste perception demonstrated marked positive changes in the study group. Specifically, olfactory threshold and total diagnostic indicator (TDI) scores improved significantly after PPI therapy, while taste perception showed modest improvement, although not statistically significant.
These findings suggest that PPIs are effective in managing LPR symptoms and can positively influence olfactory function, highlighting the multifactorial benefits of this treatment. The lack of significant changes in nasal resistance suggests that PPIs may not have a direct effect on nasal patency, but they may help alleviate related symptoms such as post-nasal drip and throat irritation.
Although the study's small sample size and reliance on subjective assessments present limitations, the results provide valuable insights into the effectiveness of PPIs in treating LPR and their potential impact on other related functions, such as smell and taste. Further research with larger sample sizes and longer treatment periods is warranted to confirm these findings and explore additional therapeutic avenues.
In summary, PPI therapy continues to show promise as an effective treatment for LPR symptoms, with a positive effect on olfactory function. Further studies are needed to fully understand the impact of PPI therapy on taste perception, nasal patency, and other related symptoms. The results of this study provide important contributions to the current understanding of LPR treatment and its broader effects on patients, and they lay the groundwork for future research in this area. The findings presented in this manuscript.
TABLE 1.
Control group measurements
TABLE 2.
Comparison of control and study groups before treatment measurements with the t-test
TABLE 3.
Comparison of control and study groups before treatment measurements with Mann-Whitney test
TABLE 4.
Values of the study group before and after treatment
TABLE 5.
Comparison of values obtained in the study group before and after antireflux therapy
FIGURE 1.
Comparison of nasal patency values before and after antireflux treatment
FIGURE 2.
Comparison of results of measurements of Sniffin’ sticks test before and after antireflux treatment
FIGURE 3.
Comparison of measurements of self-assessment of nasal symptoms and taste before and after antireflux treatment
Contributor Information
Vasiliki FLOROU, ENT Department, “G Gennimatas” General Hospital, Thessaloniki, Greece.
Nikos KAMARGIANNIS, ENT Department, “G Gennimatas” General Hospital, Thessaloniki, Greece.
Ioannis BIZAKIS, Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
Charalampos SKOULAKIS, Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
Jiannis HAJIIOANNOU, Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
References
- 1.Katle EJ, Hatlebakk JG, Steinsvag S. Gastroesophageal reflux and rhinosinusitis. Curr Allergy Asthma Rep. 2013;13:218–223. doi: 10.1007/s11882-013-0340-5. [DOI] [PubMed] [Google Scholar]
- 2.Poelmans J, Tack J, Feenstra L. Chronic middle ear disease and gastroesophageal reflux disease: a causal relation? Otol Neurotol. 2001;22:447–450. doi: 10.1097/00129492-200107000-00005. [DOI] [PubMed] [Google Scholar]
- 3.Dagli E, Yuksel A, Kaya M, et al. Association of Oral Antireflux Medication With Laryngopharyngeal Reflux and Nasal Resistance. JAMA Otolaryngol Head Neck Surg. 2017;143:478–483. doi: 10.1001/jamaoto.2016.4127. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Ford CN. Evaluation and management of laryngopharyngeal reflux. JAMA. 2005;294:1534–1540. doi: 10.1001/jama.294.12.1534. [DOI] [PubMed] [Google Scholar]
- 5.Belafsky PC, Postma GN, Koufman JA. The validity and reliability of the reflux finding score (RFS). Laryngoscope. 2001;111:1313–1317. doi: 10.1097/00005537-200108000-00001. [DOI] [PubMed] [Google Scholar]
- 6.Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the reflux symptom index (RSI). J Voice. 2002;16:274–277. doi: 10.1016/s0892-1997(02)00097-8. [DOI] [PubMed] [Google Scholar]
- 7.Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. New Jersey: Lawrence Erlbaum Associates. 1988.
- 8.Clement PA, Gordts F, Standardisation Committee on Objective Assessment of the Nasal Airway IRS, Ers. Consensus report on acoustic rhinometry and rhinomanometry. Rhinology. 2005;43:169–179. [PubMed] [Google Scholar]
- 9.Doty RL, Mishra A. Olfaction and its alteration by nasal obstruction, rhinitis, and rhinosinusitis. Laryngoscope. 2001;111:409–423. doi: 10.1097/00005537-200103000-00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Firestein S. How the olfactory system makes sense of scents. Nature. 2001;413:211–218. doi: 10.1038/35093026. [DOI] [PubMed] [Google Scholar]
- 11.Lupa M, DelGaudio JM. Evidence-Based Practice Reflux in Sinusitis. Otolaryngol Clin North Am. 2012;45:983–992. doi: 10.1016/j.otc.2012.06.004. [DOI] [PubMed] [Google Scholar]
- 12.Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope 1991. [DOI] [PubMed]
- 14.Florou V, Karkos PD, Marini K, et al. Laryngopharyngeal Reflux and Olfaction Disorders. Is There Any Connection? A Scoping Review. Maedica. 2022;17:471–480. doi: 10.26574/maedica.2022.17.2.471. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Altundag A, Cayonu M, Kayabasoglu G, et al. The evaluation of olfactory function in individuals with chronic halitosis. Chem Senses. 2015;40:47–51. doi: 10.1093/chemse/bju058. [DOI] [PubMed] [Google Scholar]
- 16.Devanand DP. Olfactory Identification Deficits, Cognitive Decline, and Dementia in Older Adults. Am J Geriatr Psychiatry. 2016;24:1151–1157. doi: 10.1016/j.jagp.2016.08.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Emre Dinc M, Dalgic A, Avincsal MO, et al. An assessment of olfactory function in patients with laryngopharyngeal reflux disease. Acta Otolaryngol. 2017;137:71–77. doi: 10.1080/00016489.2016.1211318. [DOI] [PubMed] [Google Scholar]
- 18.Gunbey E, Goren I, Unal R, Yilmaz M. An evaluation of olfactory function in adults with gastro-esophageal reflux disease. Acta Otolaryngol. 2016;136:214–218. doi: 10.3109/00016489.2015.1099735. [DOI] [PubMed] [Google Scholar]
- 19.Ozdek A, Cirak MY, Samim E, et al. A possible role of Helicobacter pylori in chronic rhinosinusitis: a preliminary report .Laryngoscope, 2003. [DOI] [PubMed]
- 20.Koc C, Arikan OK, Atasoy P, Aksoy A. Prevalence of Helicobacter pylori in patients with nasal polyps: a preliminary report. Laryngoscope, 2004. [DOI] [PubMed]
- 21.Üstün Bezgin S, Çakabay T, Irak K, et al. Association of Helicobacter pylori infection with olfactory function using smell identification screening test .Eur Arch Otorhinolaryngol, 2017. [DOI] [PubMed]