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Sensitivity, Specificity, and Reproducibility of the Brazilian Portuguese Version of the Reflux Symptom Index
ARTICLE IN PRESS
Sensitivity, Specificity, and Reproducibility of the Brazilian Portuguese Version of the Reflux Symptom Index Claudia A. Eckley, and Rodrigo Tangerina, S~ao Paulo, Brazil Summary: Introduction. The diagnosis of laryngopharyngeal reflux is controversial. There is currently no gold standard, so it relies mainly on suspicious clinical symptoms and videolaryngoscopic findings. Unfortunately these signs and symptoms are common to other causes of chronic laryngitis. Scoring systems have been proposed to reduce subjectivity in clinical diagnosis. The most widely used and accepted is the Reflux Symptom Index, which has already been translated into over 10 other languages. Objective. Study the psychometric properties of the Brazilian Portuguese version of the Reflux Symptom Index (Indice de Sintomas de Refluxo - ISR). Methods. One hundred and fifty-four adults, 88 with laryngopharyngeal reflux and 66 healthy controls, were studied over a 6-month period, responding to the ISR after thoroughly investigated on possible other causes of chronic laryngitis and the presence of gastroesophageal disease. Test and retest reliability was addressed by reapplying the score to a random subgroup of 101 subjects. Results. The ISR of subjects was significantly higher than that of controls (Student t test for independent samples, P < 0.001). The ISR also showed high temporal stability and reproducibility (ICC of 0.988 with a confidence interval of 0.982−0.992). The ISR at a cutoff of 13 points presented a sensitivity of 78.4%, a specificity of 95.4%, a false negative of 4.55%, a false positive of 21.59%, a positive predictive value of 95.83%, and a negative predictive value of 86.93%. Conclusion. The ISR proved to be a valid and reliable diagnostic tool. Key Words: Reflux laryngitis−Diagnosis−Symptoms−Differential diagnosis.
INTRODUCTION The diagnosis of laryngopharyngeal reflux (LPR) is controversial.1-4 Traditional diagnostic instruments such as esophagogastroduodenoscopy (EGD) and prolonged esophageal monitoring (24-hour double-probe pH-metry or pH-impedance tests—MII-pH) show low sensitivity to this atypical form of gastroesophageal disease (GERD).1,2,5-8 Other diagnostic tools such as dosing salivary pepsin as a biomarker for LPR has found growing interest in recent years, although questions remain about its optimal timing, location, and threshold values.9,10 Thus, there is currently no gold standard for the diagnosis of LPR,1-8 which relies mainly on clinical symptoms, videolaryngoscopic findings, and a positive therapeutic trial with proton pump inhibiors.1,3,8 However, such symptoms and signs are also common to a number of other conditions that may affect the pharynx and larynx, such as infection, vocal abuse or misuse, allergies, alcohol and tobacco abuse, and neuropsychiatric disorders.1-8,11 In order to minimize subjectivity, a number of instruments have been designed with the purpose of diagnosing LPR.1,2,8,12-17 The most widely used in clinical practice were proposed by Belafsky et al: the Reflux Finding Score (RFS)16 designed to assess videolaryngoscopic signs suggestive of the disease, and the Reflux Symptom Index (RSI)17 Accepted for publication August 13, 2019. From Diagnostic Laboratories Fleury Medicina e Sa ude S~ao Paulo, Brazil. From the Otolaryngology Division, Fleury Medicina e Sa ude, S~ao Paulo, Brazil. Address correspondence and reprint requests to Claudia A. Eckley, Otolaryngology Division, Fleury Medicina e Sa ude, Av. Vereador Jose Diniz 3457. Cj 501, S~ao Paulo, Brazil. E-mail: claudia.eckley@grupofleury.com.br Journal of Voice, Vol. &&, No. &&, pp. &&−&& 0892-1997 © 2019 The Voice Foundation. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jvoice.2019.08.012
a questionnaire validated for clinical symptoms related to LPR. The RSI, proposed by Belafsky et al in 2002,16 is a nine subdomain questionnaire based on the most common symptoms associated with LPR. Scores range from 0 to 45, whereas scores above 13 are considered positive for LPR.16 This instrument has been widely used in the international literature for both diagnosis and assessment of treatment outcome.1,2,18-20 The objective of using such an instrument is to minimize subjectivity, and its quality is determined based on its reliability, internal consistency, and validity.15-16 Previous research has proven the RSI to have high psychometric properties, which allows its reliable use in clinical practice.18-29 Several translations and adaptations of the RSI into other languages have been published, such as Hebrew,20 Italian,21 Greek,22 Arabic,23 Chinese,25 French,26 Filipino,27 Polish,28 Spanish,29 and Turkish30 showing high psychometric properties and proving a reliable, reproducible clinical method of diagnosing and following clinical outcome in patients with LPR.2,13,15-30 It was also translated and culturally adapted into Brazilian Portuguese in 2015,24 but still lacks proper validation (Figure 1). The objective of the current study was to assess the reliability and reproducibility of the Brazilian Portuguese version of the RSI as a diagnostic tool.
MATERIALS AND METHODS The study was conducted in accordance with the principles of the Declaration of Helsinki and approval was granted by the Institutional Ethics Committee for Research in Humans (IFSP#3.244.947). The studied population consisted of
ARTICLE IN PRESS 2
Journal of Voice, Vol. &&, No. &&, 2019
FIGURE 1. Brazilian Portuguese version of the RSI.24 adults over 18 and under 70 years of age that consented in participating in the current protocol after proper information on its objectives and methods. A study group was formed by patients with symptoms and videolaryngoscopic signs suggestive of LPR19 corroborated by a positive test for GERD/LPR (prolonged esophageal pH monitoring test and/or upper digestive endoscopy—EGD). The control group consisted of adults with comparable age and gender, no clinical symptoms or signs of GERD/LPR and a negative objective GERD test. Because chronic laryngitis can be associated with a number of extrinsic and intrinsic irritants, the current studied population was carefully selected to avoid any other known factors that may cause similar laryngopharyngeal symptoms and inflammatory signs. Exclusion criteria were acute or chronic rhinitis or rhinosinusitis, history of snoring or obstructive sleep apnea, previous surgery or radiation to the head and neck or digestive tract, alcohol and tobacco abuse, and any other present or
previously treated laryngeal disease or lesion.32 Patients who were experiencing acute inflammatory symptoms of the upper airways at the time of inclusion were also excluded from the study.
Diagnosing LPR Initially only patients with objective proof of reflux ascending into the upper esophagus and pharynx (positive prolonged double-probe pH-metry or MII-pH tests) were considered for the study. However, during the selection period, it was noted that a number of patients with chronic laryngitis of no other probable cause were also found to have erosive esophagitis on EGD. These patients with classical GERD (erosive esophagitis) were compared to the subset of patients with positive esophageal pH studies, and no significant differences were found between these groups in either gender, age, RFS, or RSI scores (Table 1). Therefore,
TABLE 1. Comparison of Patient Data and RSI Scores Between Subjects With Positive Prolonged Esophageal Monitoring Studies (Double-Probe pH-metry or MII-pH Studies) and Positive EGD (Erosive Esophagitis or Barret’s Esophagus)
RSI score
Diagnostic Method
N
EGD
30
pH-metry/MII-pH
58
Mean 17.97 [14.74, 21.36] 17.62 [15.66, 19.61]
SD 9.97 3.08
Median 17.00 [13.00, 19.50] 17.00 [17.00, 17.00]
Min.
Max.
P
E.S.
4.00
42.00
0.864
0.039*
2.00
43.00
Abbreviations: EGD, upper digestive endoscopy; E.S., effect size; Max., maximum; Min., minimum; SD, standard deviation. Student’s t test for independent samples. *Statistically significant value at 5% level (P ≤ 0.05).
ARTICLE IN PRESS Claudia A. Eckley and Rodrigo Tangerina
3
Brazilian Portuguese version of RSI
the authors considered both subsets of patients as representative of reflux-related chronic laryngitis. Videolaryngoscopic signs of LPR were assessed using the RSI, and scores above 7 were considered suggestive of LPR.16,19 EGD was considered positive for GERD when erosive esophagitis or Barret’s esophagus were present.1-3 Esophageal double-probe pH-metry was considered positive for proximal reflux when there was any single pH drop below 5 at the proximal probe preceded by a distal drop in esophageal pH below 4, regardless of its duration.4-6,19 Reflux episodes in the MII studies were characterized as either pure liquid or mixed liquid-gas, and as acid, nonacid, or weakly acid. Proximal pathological reflux was defined as episodes reaching the proximal pH sensor with a pH ≤ 5, regardless of its duration.7 Distal pathological reflux was established according to the manufacturer’s guidelines for both pH-metry and MII studies.5-7,19
Validation For validation of the Brazilian version of the RSI, a group of patients with LPR was compared to a group of healthy controls. Internal consistency and validity of the Brazilian version of the RSI were tested by comparing patients to healthy controls. Reproducibility and temporal stability were assessed by retesting a random sample of patients and controls 24−48 hours after the original test. Statistical analysis was carried out using commercially available software SPSS (Statistical Package for Social Sciences version 25.0, IBM Corp., Armonk, NY). Agreement between the total test and retest RSI scores was studied using the Interclass Correlation test (ICC). Comparison between patients and controls were made using nonparametric tests and multivariate analysis was carried out using ANOVA. Significance level was established at P < 0.05. RESULTS Over an 8-month period, the Brazilian Portuguese version of the RSI (“I ndice de Sintomas de Refluxo −ISR”) (Figure 1) was applied to a group of 154 subjects: 88 patients with LPR with a mean age of 52.3 years (SD § 10.89), 34 females and 54 males; and 66 controls with a mean age of 47.33 years (SD § 12.84), 40 females and 26 males. Controls had no symptoms or videolaryngoscopic signs of LPR and had no
abnormalities on objective GERD tests. Although patients and controls showed a statistically significant difference in age and gender, this did not influence final results. The Brazilian Portuguese version of the RSI showed high internal consistency for differentiating between healthy individuals and those with LPR (Table 2). A statistically significant difference was observed between the Brazilian Portuguese version of the RSI scores of patients (mean 17.74 § 8.93) and of controls (mean 6.48 § 4.17) (Student t test for independent samples, P < 0.001; Figure 2). For assessment of reproducibility and temporal stability of the translated RSI, 101 subjects (46 patients and 55 controls) were retested 24−72 hours after the original test. These groups were similar in age (P = 0.51) and gender (P = 0.09). The interclass correlation coefficient (ICC) comparing test and retest was 0.988 with a confidence interval of 0.982−0.992. According to the receiver operating characteristic curve analysis (ROC), the area under curve of the Brazilian Portuguese version of the RSI was 0.887 (Figure 3). The optimal cut-off value was 12.5 with a sensitivity of 82.6% and a specificity of 84.6%. However, because the RSI does not consider half points, the cuffoff for the Brazilian Portuguese version of the RSI was established at 13 points presenting a sensitivity of 78.41%, a specificity of 95.45%, a false negative of 4.55%, a false positive of 21.59%, a positive predictive value of 95.83%, a negative predictive value of 76.83%, and an efficiency of 86.93%. DISCUSSION The diagnosis of LPR remains a great challenge for clinicians, as symptoms of chronic laryngitis are common and can be caused by a number of allergic, infectious, irritant, or even psychogenic or neurogenic triggers. In most patients, there is an association of different causes, which adds to the diagnostic challenge. Ideally, there should be a cost-effective, minimally invasive, and highly sensitive objective test for LPR. Unfortunately, that is not the case. Esophageal pH-impedance and pH-metry are costly, invasive, and have a suboptimal sensitivity.1,2,31-36 Salivary pepsin tests, although significantly less expensive and invasive, are still being validated and have not become a standard in clinical practice.9,10 These difficulties have motivated the growing interest in developing better clinical diagnostic tools.
TABLE 2. Descriptive Values and Comparative Analysis of RSI Score Regarding Group Variable
Group
N
RSI score
SG
88
CG
66
Mean 17.74 [15.90, 19.63] 6.48 [5.52, 7.44]
SD 8.93 4.17
Median 17.00 [16.50, 17.00] 6.50 [6.00, 8.00]
Min.
Max.
P
E.S.
2.00
43.00
<0.001*
2.699
0.00
17.00
* Statistically significant value at 5% level (P ≤ 0.05). Abbreviations: CG, control group; E.S., effect size; Max., maximum; Min., minimum; SD, standard deviation; SG, study group. Student’s t test for independent samples.
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FIGURE 2. Comparison of Brazilian RSI scores between patients and healthy controls.
Journal of Voice, Vol. &&, No. &&, 2019
prognostic tool over time has increased the validity of its construct, even if the original paper had a small sample size.16,17,32,33 Likewise, the other psychometric properties of the RSI were strengthened through the reliability studies performed with this and the other translated versions of the RSI.18-31 The internal consistency of the RSI translated into Brazilian Portuguese was high and comparable to that observed in translations to other languages, such as Italian, Greek, Arabic, Spanish, and Turkish.21-23,27,30 Internal consistency was not calculated in the original study.16 Reproducibility of the Brazilian Portuguese version of the RSI was also high and comparable to that of the original version16 and to other translations.18,21,23,27-30 When attempting to diagnose LPR, one must be very careful to rule out other possible causes of chronic irritation of the larynx and pharynx. If diligent history and a careful physical examination are carried out, such other causes can generally be identified. Under a strong clinical suspicion of LPR, the RSI has proven to be a helpful diagnostic and prognostic tool.31,32,34-36 This notion is corroborated by the constantly growing numbers of translations of RSI in recent years.20-30 Likewise, the current study found the Brazilian version of the Reflux Symptom Index (“I ndice de Sintomas de Refluxo” or “ISR”) to be a valid and reliable diagnostic tool.
SUPPLEMENTARY MATERIALS Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j. jvoice.2019.08.012.
REFERENCES
FIGURE 3. ROC curve for the ideal cutoff of the Brazilian Portuguese version of the RSI.
Although the RSI is not an ideal tool, it has been widely used throughout the world to assist in the diagnosis of LPR.1-7,17,20,34-36 In fact, in the past 5 years, it has been translated and validated into over seven different languages,24-30 and altogether since it was proposed in 200216 more than 10 languages.20-30 Cross-cultural influences affect perceptions and health practices.28 Many challenges exist in obtaining valid and reliable measurement instruments that can be culturally sensitive and adaptable.32,33 The fact that a questionnaire has been tested in previous research and published in peer-reviewed journals does not make it necessarily valid and reliable.32 However, the great number of studies that tested the RSI as a diagnostic and
1. Lechien JR, Akst LM, Hamdan AL, et al. Evaluation and management of laryngopharyngeal reflux disease: state of the art review. Otolaryngol Head Neck Surg. 2019;160:762–782. 2. Asaoka D, Nagahara A, Matsumoto K, et al. Current perspectives on reflux laryngitis. Clin J Gastroenterol. 2014;7:471–475. 3. Hawkshaw MJ, Pebdani P, Sataloff RT. Reflux laryngitis: an update, 2009−2012. J Voice. 2013;27:486–494. 4. Moraes-Filho JPP, Cecconello I, Gama-Rodrigues J, et al. Brazilian consensus on gastroesophageal reflux disease: proposals for assessment, classification, and management. Am J Gastroenterol. 2002;97: 241–248. 5. Ylitalo R, Lindestad PA, Ramel S. Symptoms, laryngeal findings, and 24 hour pH monitoring in patients with suspected gastroesophago pharyngeal reflux. Laryngoscope. 2013;111:1735–1741. 6. Lechien JR, Akst LM, Hamdan AL, et al. Evaluation and management of laryngopharyngeal reflux disease: state of the art review. Otolaryngol Head Neck Surg. 2019;160:762–782. 7. Lee B, Kim G, Ryu D, et al. Combined dual channel impedance/pHmetry in patients with suspected laryngopharyngeal reflux. J Neurogastroenterol Motil. 2010;16:157–165. 8. Koufman JA, Aviv JE, Casiano RR, et al. Laryngopharyngeal reflux: position statement of the committee on speech, voice, and swallowing disorders of the American Academy of Otolaryngology-Head and Neck Surgery. Otolaryngol Head Neck Surg. 2002;127:32–35.
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9. Calvo-Henríquez C, Ruano-Ravina A, Vaamonde P, et al. Is pepsin a reliable marker of laryngopharyngeal reflux? A systematic review. Otolaryngol Head Neck Surg. 2017;157:385–391. 10. Wang J, Zhao Y, Ren J, et al. Pepsin in saliva as a diagnostic biomarker in laryngopharyngeal reflux: a meta-analysis. Eur Arch Otorhinolaryngol. 2018;275:671–678. 11. Carrau RL, Khidr A, Crawley JA, et al. The impact of laryngopharyngeal reflux on patient-reported quality of life. Laryngoscope. 2004;114:670–674. 12. Carrau RL, Khidr A, Gold KF. Validation of a quality-of-life instrument for laryngopharyngeal reflux. Arch Otolaryngol Head Neck Surg. 2005;131:315–320. 13. Mearin F, Ponce J, Ponce M, et al. Frequency and clinical implication of supraesophageal and dyspeptic symptoms in gastroesophageal reflux disease. Eur J Gastroenterol Hepatol. 2012;24:665–674. 14. Simons JP, Rosen CA, Casselbrant CA, et al. Comparison of pediatric voice outcome survey, reflux symptom index, reflux finding score, and esophageal biopsy results. Arch Otolaryngol Head Neck Surg. 2008;34: 837–841. 15. Belafsky PC, Postma GN, Koufman JA. The validity and reliability of the reflux finding score (RFS). Laryngoscope. 2001;111:1313–1317. 16. Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the reflux symptom index (RSI). Laryngoscope. 2002;16:274–277. 17. Habermann W, Schmid C, Neumann K, et al. Reflux symptom index and reflux finding score in otolaryngologic practice. J Voice. 2012;26: e123–e127. 18. Almeida AGDP, Saliture TBS, Silva ASD, et al. Translation and cultural adaptation of the reflux finding score into Brazilian Portuguese. Braz J Otorhinolaryngol. 2013;79:47–53. 19. Oyer SL, Anderson LC, Halum SL. Influence of anxiety and depression on the predictive value of the reflux symptom index. Ann Otol Rhinol Laryngol. 2009;118:687. 20. Cohen JT, Gil Z, Fliss DM. The reflux symptom index: a clinical tool for the diagnosis of laryngopharyngeal reflux. Harefuah. 2005;144:826–912. 21. Schindler A, Mozzanica F, Ginocchio D, et al. Reliability and clinical validity of the Italian reflux symptom index. J Voice. 2010;24:354–358. 22. Printza A, Kyrgidis A, Oikonomidou E, et al. Assessing laryngopharyngeal reflux symptoms with the reflux symptom index validation and prevalence in the Greek population. Otolaryngol Head Neck Surg. 2011;45:974–980. 23. Farahat M, Malki K H, Mesallam TA. Development of the Arabic version of reflux symptom index. J Voice. 2012;26:814–815.
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24. Saliture TB, Duprat AC, Eckley CA. Tradu¸c a~o e Adapta¸c a~o Cultural do Reflux Symptom Index para o Portugu^es Brasileiro. (Thesis). S~ao Paulo, Brazil: Santa Casa School of Medicine and Hospitals; 2015:81. 25. Li J, Zhang L, Zhang C, et al. Linguistic adaptation, reliability, validation, and responsivity of the Chinese version of reflux symptom index. J Voice. 2016;30:104–108. 26. Lechien JR, Huet K, Finck C, et al. Validity and reliability of a French version of reflux symptom index. J Voice. 2017;31:512.e1–512.e7. 27. Lape~ na Jr. JFF, Ambrocio GMC, Carrillo RJD. Validity and reliability of the Filipino reflux symptom index. J Voice. 2017;31:387.e11– 387.e16. 28. W»odarczyk E, Miaskiewicz B, Szkie»kowska A, et al. The use of RSI and RFS questionnaires in the Polish language version. Otolaryngol Pol. 2018;73:1–5. 16. 29. Calvo-Henríquez C, Ruano-Ravina A, Vaamonde P, et al. Translation and validation of the reflux symptom index to Spanish. J Voice. 2019;33:807.e1–807.e5. 30. Akbulut S, Aydinli FE, Ku¸sc¸ u O, et al. Reliability and validity of the Turkish reflux symptom index. J Voice. 2019. https://doi.org/10.1016/j. jvoice.2019.05.015. 31. Watson NA, Kwame I, Oakeshott P, et al. Comparing the diagnosis of laryngopharyngeal reflux between the reflux symptom index, clinical consultation and reflux finding score in a group of patients presenting to an ENT clinic with an interest in voice disorders: a pilot study in thirty-five patients. Clin Otolaryngol. 2013;38:329–333. 32. Guillemin F, Bombardier C, Beaton D. Cross-cultural adaptation of health-related quality of life measures: literature review and proposed guidelines. J Clin Epidemiol. 1993;46:1417–1432. 33. Sousa VD, Rojjanasrira W. Translation, adaptation and validation of instruments or scales for use in cross-cultural health care research: a clear and user friendly guideline. J Eval Clin Pract. 2011;17:268–274. 34. Vardar R, Varis A, Bayrakci B, et al. Relationship between history, laryngoscopy and esophagogastroduodenoscopy for diagnosis of laryngopharyngeal reflux in patients with typical GERD. Eur Arch Otorhinolaryngol. 2012;269:187–191. 35. Martinucci I, Albano E, Marchi S, et al. Extra-esophageal presentation of gastroesophageal reflux disease: new understanding in a new era. Minerva Gastroenterol Dietol. 2017;63:221–234. 36. Hom C, Vaezi MF. Extra-esophageal manifestations of gastroesophageal reflux disease: diagnosis and treatment. Drugs. 2013;73: 1281–1295.
Sensitivity, Specificity, and Reproducibility of the Brazilian Portuguese Version of the Reflux Symptom Index Claudia A. Eckley, and Rodrigo Tangerina, S~ao Paulo, Brazil Summary: Introduction. The diagnosis of laryngopharyngeal reflux is controversial. There is currently no gold standard, so it relies mainly on suspicious clinical symptoms and videolaryngoscopic findings. Unfortunately these signs and symptoms are common to other causes of chronic laryngitis. Scoring systems have been proposed to reduce subjectivity in clinical diagnosis. The most widely used and accepted is the Reflux Symptom Index, which has already been translated into over 10 other languages. Objective. Study the psychometric properties of the Brazilian Portuguese version of the Reflux Symptom Index (Indice de Sintomas de Refluxo - ISR). Methods. One hundred and fifty-four adults, 88 with laryngopharyngeal reflux and 66 healthy controls, were studied over a 6-month period, responding to the ISR after thoroughly investigated on possible other causes of chronic laryngitis and the presence of gastroesophageal disease. Test and retest reliability was addressed by reapplying the score to a random subgroup of 101 subjects. Results. The ISR of subjects was significantly higher than that of controls (Student t test for independent samples, P < 0.001). The ISR also showed high temporal stability and reproducibility (ICC of 0.988 with a confidence interval of 0.982−0.992). The ISR at a cutoff of 13 points presented a sensitivity of 78.4%, a specificity of 95.4%, a false negative of 4.55%, a false positive of 21.59%, a positive predictive value of 95.83%, and a negative predictive value of 86.93%. Conclusion. The ISR proved to be a valid and reliable diagnostic tool. Key Words: Reflux laryngitis−Diagnosis−Symptoms−Differential diagnosis.
INTRODUCTION The diagnosis of laryngopharyngeal reflux (LPR) is controversial.1-4 Traditional diagnostic instruments such as esophagogastroduodenoscopy (EGD) and prolonged esophageal monitoring (24-hour double-probe pH-metry or pH-impedance tests—MII-pH) show low sensitivity to this atypical form of gastroesophageal disease (GERD).1,2,5-8 Other diagnostic tools such as dosing salivary pepsin as a biomarker for LPR has found growing interest in recent years, although questions remain about its optimal timing, location, and threshold values.9,10 Thus, there is currently no gold standard for the diagnosis of LPR,1-8 which relies mainly on clinical symptoms, videolaryngoscopic findings, and a positive therapeutic trial with proton pump inhibiors.1,3,8 However, such symptoms and signs are also common to a number of other conditions that may affect the pharynx and larynx, such as infection, vocal abuse or misuse, allergies, alcohol and tobacco abuse, and neuropsychiatric disorders.1-8,11 In order to minimize subjectivity, a number of instruments have been designed with the purpose of diagnosing LPR.1,2,8,12-17 The most widely used in clinical practice were proposed by Belafsky et al: the Reflux Finding Score (RFS)16 designed to assess videolaryngoscopic signs suggestive of the disease, and the Reflux Symptom Index (RSI)17 Accepted for publication August 13, 2019. From Diagnostic Laboratories Fleury Medicina e Sa ude S~ao Paulo, Brazil. From the Otolaryngology Division, Fleury Medicina e Sa ude, S~ao Paulo, Brazil. Address correspondence and reprint requests to Claudia A. Eckley, Otolaryngology Division, Fleury Medicina e Sa ude, Av. Vereador Jose Diniz 3457. Cj 501, S~ao Paulo, Brazil. E-mail: claudia.eckley@grupofleury.com.br Journal of Voice, Vol. &&, No. &&, pp. &&−&& 0892-1997 © 2019 The Voice Foundation. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jvoice.2019.08.012
a questionnaire validated for clinical symptoms related to LPR. The RSI, proposed by Belafsky et al in 2002,16 is a nine subdomain questionnaire based on the most common symptoms associated with LPR. Scores range from 0 to 45, whereas scores above 13 are considered positive for LPR.16 This instrument has been widely used in the international literature for both diagnosis and assessment of treatment outcome.1,2,18-20 The objective of using such an instrument is to minimize subjectivity, and its quality is determined based on its reliability, internal consistency, and validity.15-16 Previous research has proven the RSI to have high psychometric properties, which allows its reliable use in clinical practice.18-29 Several translations and adaptations of the RSI into other languages have been published, such as Hebrew,20 Italian,21 Greek,22 Arabic,23 Chinese,25 French,26 Filipino,27 Polish,28 Spanish,29 and Turkish30 showing high psychometric properties and proving a reliable, reproducible clinical method of diagnosing and following clinical outcome in patients with LPR.2,13,15-30 It was also translated and culturally adapted into Brazilian Portuguese in 2015,24 but still lacks proper validation (Figure 1). The objective of the current study was to assess the reliability and reproducibility of the Brazilian Portuguese version of the RSI as a diagnostic tool.
MATERIALS AND METHODS The study was conducted in accordance with the principles of the Declaration of Helsinki and approval was granted by the Institutional Ethics Committee for Research in Humans (IFSP#3.244.947). The studied population consisted of
ARTICLE IN PRESS 2
Journal of Voice, Vol. &&, No. &&, 2019
FIGURE 1. Brazilian Portuguese version of the RSI.24 adults over 18 and under 70 years of age that consented in participating in the current protocol after proper information on its objectives and methods. A study group was formed by patients with symptoms and videolaryngoscopic signs suggestive of LPR19 corroborated by a positive test for GERD/LPR (prolonged esophageal pH monitoring test and/or upper digestive endoscopy—EGD). The control group consisted of adults with comparable age and gender, no clinical symptoms or signs of GERD/LPR and a negative objective GERD test. Because chronic laryngitis can be associated with a number of extrinsic and intrinsic irritants, the current studied population was carefully selected to avoid any other known factors that may cause similar laryngopharyngeal symptoms and inflammatory signs. Exclusion criteria were acute or chronic rhinitis or rhinosinusitis, history of snoring or obstructive sleep apnea, previous surgery or radiation to the head and neck or digestive tract, alcohol and tobacco abuse, and any other present or
previously treated laryngeal disease or lesion.32 Patients who were experiencing acute inflammatory symptoms of the upper airways at the time of inclusion were also excluded from the study.
Diagnosing LPR Initially only patients with objective proof of reflux ascending into the upper esophagus and pharynx (positive prolonged double-probe pH-metry or MII-pH tests) were considered for the study. However, during the selection period, it was noted that a number of patients with chronic laryngitis of no other probable cause were also found to have erosive esophagitis on EGD. These patients with classical GERD (erosive esophagitis) were compared to the subset of patients with positive esophageal pH studies, and no significant differences were found between these groups in either gender, age, RFS, or RSI scores (Table 1). Therefore,
TABLE 1. Comparison of Patient Data and RSI Scores Between Subjects With Positive Prolonged Esophageal Monitoring Studies (Double-Probe pH-metry or MII-pH Studies) and Positive EGD (Erosive Esophagitis or Barret’s Esophagus)
RSI score
Diagnostic Method
N
EGD
30
pH-metry/MII-pH
58
Mean 17.97 [14.74, 21.36] 17.62 [15.66, 19.61]
SD 9.97 3.08
Median 17.00 [13.00, 19.50] 17.00 [17.00, 17.00]
Min.
Max.
P
E.S.
4.00
42.00
0.864
0.039*
2.00
43.00
Abbreviations: EGD, upper digestive endoscopy; E.S., effect size; Max., maximum; Min., minimum; SD, standard deviation. Student’s t test for independent samples. *Statistically significant value at 5% level (P ≤ 0.05).
ARTICLE IN PRESS Claudia A. Eckley and Rodrigo Tangerina
3
Brazilian Portuguese version of RSI
the authors considered both subsets of patients as representative of reflux-related chronic laryngitis. Videolaryngoscopic signs of LPR were assessed using the RSI, and scores above 7 were considered suggestive of LPR.16,19 EGD was considered positive for GERD when erosive esophagitis or Barret’s esophagus were present.1-3 Esophageal double-probe pH-metry was considered positive for proximal reflux when there was any single pH drop below 5 at the proximal probe preceded by a distal drop in esophageal pH below 4, regardless of its duration.4-6,19 Reflux episodes in the MII studies were characterized as either pure liquid or mixed liquid-gas, and as acid, nonacid, or weakly acid. Proximal pathological reflux was defined as episodes reaching the proximal pH sensor with a pH ≤ 5, regardless of its duration.7 Distal pathological reflux was established according to the manufacturer’s guidelines for both pH-metry and MII studies.5-7,19
Validation For validation of the Brazilian version of the RSI, a group of patients with LPR was compared to a group of healthy controls. Internal consistency and validity of the Brazilian version of the RSI were tested by comparing patients to healthy controls. Reproducibility and temporal stability were assessed by retesting a random sample of patients and controls 24−48 hours after the original test. Statistical analysis was carried out using commercially available software SPSS (Statistical Package for Social Sciences version 25.0, IBM Corp., Armonk, NY). Agreement between the total test and retest RSI scores was studied using the Interclass Correlation test (ICC). Comparison between patients and controls were made using nonparametric tests and multivariate analysis was carried out using ANOVA. Significance level was established at P < 0.05. RESULTS Over an 8-month period, the Brazilian Portuguese version of the RSI (“I ndice de Sintomas de Refluxo −ISR”) (Figure 1) was applied to a group of 154 subjects: 88 patients with LPR with a mean age of 52.3 years (SD § 10.89), 34 females and 54 males; and 66 controls with a mean age of 47.33 years (SD § 12.84), 40 females and 26 males. Controls had no symptoms or videolaryngoscopic signs of LPR and had no
abnormalities on objective GERD tests. Although patients and controls showed a statistically significant difference in age and gender, this did not influence final results. The Brazilian Portuguese version of the RSI showed high internal consistency for differentiating between healthy individuals and those with LPR (Table 2). A statistically significant difference was observed between the Brazilian Portuguese version of the RSI scores of patients (mean 17.74 § 8.93) and of controls (mean 6.48 § 4.17) (Student t test for independent samples, P < 0.001; Figure 2). For assessment of reproducibility and temporal stability of the translated RSI, 101 subjects (46 patients and 55 controls) were retested 24−72 hours after the original test. These groups were similar in age (P = 0.51) and gender (P = 0.09). The interclass correlation coefficient (ICC) comparing test and retest was 0.988 with a confidence interval of 0.982−0.992. According to the receiver operating characteristic curve analysis (ROC), the area under curve of the Brazilian Portuguese version of the RSI was 0.887 (Figure 3). The optimal cut-off value was 12.5 with a sensitivity of 82.6% and a specificity of 84.6%. However, because the RSI does not consider half points, the cuffoff for the Brazilian Portuguese version of the RSI was established at 13 points presenting a sensitivity of 78.41%, a specificity of 95.45%, a false negative of 4.55%, a false positive of 21.59%, a positive predictive value of 95.83%, a negative predictive value of 76.83%, and an efficiency of 86.93%. DISCUSSION The diagnosis of LPR remains a great challenge for clinicians, as symptoms of chronic laryngitis are common and can be caused by a number of allergic, infectious, irritant, or even psychogenic or neurogenic triggers. In most patients, there is an association of different causes, which adds to the diagnostic challenge. Ideally, there should be a cost-effective, minimally invasive, and highly sensitive objective test for LPR. Unfortunately, that is not the case. Esophageal pH-impedance and pH-metry are costly, invasive, and have a suboptimal sensitivity.1,2,31-36 Salivary pepsin tests, although significantly less expensive and invasive, are still being validated and have not become a standard in clinical practice.9,10 These difficulties have motivated the growing interest in developing better clinical diagnostic tools.
TABLE 2. Descriptive Values and Comparative Analysis of RSI Score Regarding Group Variable
Group
N
RSI score
SG
88
CG
66
Mean 17.74 [15.90, 19.63] 6.48 [5.52, 7.44]
SD 8.93 4.17
Median 17.00 [16.50, 17.00] 6.50 [6.00, 8.00]
Min.
Max.
P
E.S.
2.00
43.00
<0.001*
2.699
0.00
17.00
* Statistically significant value at 5% level (P ≤ 0.05). Abbreviations: CG, control group; E.S., effect size; Max., maximum; Min., minimum; SD, standard deviation; SG, study group. Student’s t test for independent samples.
ARTICLE IN PRESS 4
FIGURE 2. Comparison of Brazilian RSI scores between patients and healthy controls.
Journal of Voice, Vol. &&, No. &&, 2019
prognostic tool over time has increased the validity of its construct, even if the original paper had a small sample size.16,17,32,33 Likewise, the other psychometric properties of the RSI were strengthened through the reliability studies performed with this and the other translated versions of the RSI.18-31 The internal consistency of the RSI translated into Brazilian Portuguese was high and comparable to that observed in translations to other languages, such as Italian, Greek, Arabic, Spanish, and Turkish.21-23,27,30 Internal consistency was not calculated in the original study.16 Reproducibility of the Brazilian Portuguese version of the RSI was also high and comparable to that of the original version16 and to other translations.18,21,23,27-30 When attempting to diagnose LPR, one must be very careful to rule out other possible causes of chronic irritation of the larynx and pharynx. If diligent history and a careful physical examination are carried out, such other causes can generally be identified. Under a strong clinical suspicion of LPR, the RSI has proven to be a helpful diagnostic and prognostic tool.31,32,34-36 This notion is corroborated by the constantly growing numbers of translations of RSI in recent years.20-30 Likewise, the current study found the Brazilian version of the Reflux Symptom Index (“I ndice de Sintomas de Refluxo” or “ISR”) to be a valid and reliable diagnostic tool.
SUPPLEMENTARY MATERIALS Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j. jvoice.2019.08.012.
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FIGURE 3. ROC curve for the ideal cutoff of the Brazilian Portuguese version of the RSI.
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