LPR corelation

The LaryngoscopeLippincott Williams&Wilkins,Inc.©2005The American Laryngological,Rhinological and Otological Society,Inc.Correlation between Symptoms and Laryngeal Signs in Laryngopharyngeal RefluxMohammed A.Qadeer,MD;Jason Swoger,MD,MPH;Claudio Milstein,PhD;Douglas M.Hicks,PhD; Jeff Ponsky,MD;Joel E.Richter,MD;Tom I.Abelson,MD;Michael F.Vaezi,MD,PhD,MSepiObjective/Hypothesis:Laryngopharyngeal reflux (LPR)is diagnosed by the presence of laryngeal signs and symptoms.Some studies have noted that signs and symptoms may be nonspecific and may have poor correlation.However,many such studies were either observational or had short-term follow-up.Therefore, we conducted subgroup analysis of a prospective con-current controlled study with a1year follow-up to study the correlation between signs and symptoms. Study Design:Prospective study.Methods:Seventy-two patients with suspected gastroesophageal reflux disease related laryngeal symptoms/signs received a4 month trial of aggressive acid-suppressive therapy. Four month symptomatic nonresponders(<50%im-provement)with continued laryngeal inflammation and normalized esophageal acid exposure were then offered laparoscopic Nissen fundoplication.The pri-mary outcome was laryngeal symptom-sign correla-tion at1year postsurgery.Results:Twenty-five of72 (35%)patients remained unresponsive after4months of aggressive acid suppressive therapy.Ten(40%)pa-tients agreed to undergo surgical fundoplication (mean age؍50,male؍4).The most common laryn-geal symptoms were sore throat(40%),hoarseness (30%),and cough(20%),whereas the most common signs were medial arytenoid wall erythema/edema (60%),interarytenoid erythema(50%),and arytenoid complex erythema/edema(50%).At1year postfundo-plication,laryngeal symptoms improved in only1of 10(10%)patient,whereas signs improved in8of10 (80%)patients.Conclusions:There appears to be poor correlation between signs and symptoms of LPR,par-ticularly when monitoring therapeutic outcomes.In patients unresponsive to twice-daily proton-pump in-hibitor therapy for4months,further aggressive ther-apy is unlikely to bring additional symptomatic ben-efit.Key Words:Laryngopharyngeal reflux(LPR), symptom-sign correlation,twice-daily PPI, fundoplication.Laryngoscope,115:1947–1952,2005 INTRODUCTIONLaryngopharyngeal reflux(LPR)or reflux laryngitis is one of the most common extra-esophageal manifesta-tions of gastroesophageal reflux disease(GERD).1,2Popu-lation based studies found that the prevalence of symp-toms attributed to LPR was in the range of15%to20%.3,4 It is estimated that up to15%of all visits to the otolaryn-gology offices are because of manifestations of LPR.1,5,6 The symptoms that are commonly attributed to LPR are hoarseness,throat clearing,nocturnal laryngospasm, otalgia,postnasal drip,chronic cough,and dysphagia.1,7 Because many of these symptoms are nonspecific,confir-mation of the diagnosis usually requires laryngoscopic examination on which the presence of any of the following is considered LPR:erythema,edema,pseudosulcus,ven-tricular obliteration,and postcricoid hyperplasia.1How-ever,even these signs are not specific to LPR because of their high prevalence in general asymptomatic popula-tion.8,9Thus,it is possible that the presence of both symp-toms and signs might increase the likelihood of LPR diag-nosis.However,it is not known if there is symptom-sign correlation in these patients and whether this correlation could be used to monitor therapeutic outcomes.To assess the relationship between symptoms and laryngeal signs,we conducted analysis of a cohort of pa-tients who had chronic laryngitis unresponsive to aggres-sive acid suppressive therapy and having undergone lapa-roscopic fundoplication(definitive therapy for GERD) were followed for a period of1year.The aim of this analysis was to assess the strength of correlation between LPR signs and symptoms after definitive therapy of GERD.From the Department of Gastroenterology and Hepatology(M.Q.,J.S., J.E.R.,M.F.V.),Center for Swallowing and Esophageal Disorders,the Headand Neck Institute(C.M.,D.M.H.,T.I.A.),and the Department of General Surgery(J.P.),Cleveland Clinic Foundation,Cleveland,Ohio,U.S.A.Editor’s Note:This Manuscript was accepted for publication June22, 2005.Send Correspondence to Dr.Michael F.Vaezi,Department of Gas-troenterology and Hepatology,1501TVC,1301-22nd Avenue South,Nash-ville,TN37232-5280,U.S.A.E-mail:Michael.vaezi@DOI:10.1097/01.mlg.0000176547.90094.acMATERIALS AND METHODSPatient PopulationThe study cohort included the subgroup of patients who underwent laparoscopic fundoplication for chronic laryngeal symptoms after a failed4month trial of aggressive acid suppres-sive therapy.This subgroup was derived from the original cohort of patients with chronic laryngitis who were followed by the Department of Gastroenterology and Head and Neck Institute since1997.All these patients were evaluated by laryngoscopy, esophagogastroduodenoscopy,manometry,and24hour ambula-tory pH monitoring and treated with a4month trial of aggressive acid-suppressive therapy(omeprazole40mg twice daily or lan-soprazole60mg twice daily).Those who were unresponsive (Ͻ50%symptomatic improvement)to the above regimen were offered fundoplication as a definitive therapy for GERD.In the primary study,those patients who underwent fundoplication were compared with those who continued on aggressive proton-pump inhibitor(PPI)therapy for symptomatic improvement at1 year.10For the purpose of this analysis,we studied only the subgroup that underwent fundoplication and evaluated the cor-relation between laryngeal signs and symptoms at1year after fundoplication.Inclusion criteria were age greater than18years,chronic symptoms(cough,throat clearing,sore/burning throat,hoarse-ness,and globus),and laryngoscopic findings suggestive of LPR despite aggressive acid suppression.Patients were excluded from the study if they had Barrett’s esophagus,prior surgical therapy for GERD,or if they were unwilling to participate in the study.All patients meeting the inclusion criteria completed a four page nurse-administered questionnaire at the start of the study. The questionnaire consisted of demographic information,medical history,tobacco and alcohol use,current medication regimen,history of allergies,presence of other potential laryngeal irritants (asthma,sinusitis,sinus congestion,allergies,postnasal drip, viral illness,and vocal abuse),and description of specific laryn-geal symptoms.Patients were asked to report presence or ab-sence of symptoms(cough,hoarseness,throat clearing,sore throat,globus sensation,heartburn,regurgitation,problem swal-lowing,chest pain,and discomfort to talk)by answering yes or no on the questionnaire and score the severity using a scale of1to4 (1ϭrare[once a month or less];2ϭoccasional[once a week or less];3ϭfrequent[several times a week];4ϭall the time [several times daily]).After fundoplication,patients were monitored for1year.All subjects kept daily symptom diaries during the study period using the above severity scoring system.All patients also had blinded symptom assessment using a standard questionnaire at 1,3,6and12months postoperatively.Patients were asked to score their symptoms on a scale of0%to100%improvement. Response of laryngeal signs to surgical fundoplication was eval-uated at6and12months postfundoplication by a single endos-copist blinded to patients’symptomatic response status. LaryngoscopyPatients underwent a videotaped fiberoptic laryngoscopy at the Cleveland Clinic Head and Neck Institute before surgery and at6and12months postoperatively.The laryngoscopy was per-formed by one specialist(D.H.)who was blinded to patient symp-toms and group allocation.To ensure technical consistency,all examinations followed a standard protocol of subject instructions and tasks and used the same equipment.The subjects were seated comfortably and asked to sniff three sprays of a mixture of topical anesthetic and decongestant(1%neosynephrine;4%Xy-locaine)through one nostril.The flexible nasopharyngoscope (Pentax model FNL13S,Pentax Precision Instrument Corp,Ja-pan)was coupled to a color video camera(Toshiba model IK-C30A,Toshiba Corp,Japan)and was illuminated by a xenon light source(Karl Storz model610,Karl Storz Endoscopy–American Inc.,Culver City,CA).The scope was inserted into the nostril, passed along the nasal floor,and maneuvered to the oropharynx and upper hypopharynx.The subject was asked to perform a series of vegetative tasks(breathing,swallowing,coughing,sniff-ing,throat clearing)and vocal tasks(whistling,sustained phona-tion,alternate phonation/inhalation,and pitch glides)designed to allow visualization of the posterior pharyngeal wall,hypophar-ynx,and intrinsic larynx.Findings of erythema,edema,redun-dant tissue,surface irregularities,and other lesions were noted for each structure(posterior pharyngeal wall,posterior commis-sure[anterior cricoid wall],posterior cricoid wall,arytenoids com-plex,true and false vocal cords,anterior commissure,epiglottis, and aryepiglottic folds)and were recorded by the examiner on a checklist(Appendix).7,8Fig.1.Flow chart depicting the process of patient selection.TABLE I.Prevalence of Primary and Secondary Symptoms(nϭ10). Symptom Primary(%)Secondary(%) Chronic cough2010 Throat clearing010 Sore/burning throat4030 Globus010 Hoarseness3020 Dysphagia00 Other*00 None010 *Chest pain,shortness of breath,and regurgitation.Surgical InterventionAll the patients who underwent fundoplication were sub-jected to repeat pH monitoring(off-therapy),esophageal manom-etry,and barium esophagram before surgery and were docu-mented to have reflux on pH monitoring or esophagram.All these patients had their procedure performed by a single surgeon(J.P.) at the Cleveland Clinic Foundation Department of General Sur-gery.A standard360°laparoscopic Nissen fundoplication was performed in all10subjects.None of the patients required con-version to an open procedure.After fundoplication,the complete-ness of the procedure was assessed by pH monitoring and ma-nometry at3months and12months.Statistical AnalysisOverall descriptive statistics including means,medians, and standard deviations for continuous variables and frequencies for categorical variables were calculated.Symptom improvement was recorded on a scale of0%to100%.This score was further classified into1of2categories:greater than50%improvement or 50%or less improvement.Pearson’s chi-square test and Fisher’s exact test were used as appropriate to compare the proportion of patients that report greater than50%improvement in their symptoms groups.The Wilcoxon rank sum test was used to study the differences in the global assessment symptom score.A signif-icance level of.05was used in the analyses.Calculations were performed using JMP5.1software(SAS Institute,Cary,NC). RESULTSDemographicsThe original cohort consisted of72patients of which 25(35%)did not respond to aggressive PPIs,reporting less than50%symptom improvement after4months of ther-apy.Ten of these25(40%)patients agreed to enroll in this prospective surgical protocol and formed the cohort for this analysis(Fig.1).The mean age of the patients in this cohort was50(SD9.55)years.All the patients were white; males were40%and females60%.Fifty percent of the cases were ex-smokers,whereas another50%were non-smokers.Seventy percent of the patients consumed alco-hol.Baseline Laryngeal FindingsThe most common symptoms in these patients were sore throat and burning throat(40%)followed by hoarse-ness(30%)and chronic cough(20%).Sore throat was also present in significant number of patients whose main symptom was hoarseness or chronic cough(Table I).The symptoms were moderate to severe with mean severity score of3.4(SE0.8)on a scale of1to4.Seven of10(70%) of the patients had heartburn.These symptoms were per-sistent despite normalization of pH levels after4month PPI therapy.The most common signs in these patients were medial arytenoid wall erythema/edema(60%),fol-lowed by interarytenoid erythema(50%)and arytenoid complex erythema/edema(50%)(Table II).Technical Success of Surgical Procedure The surgical procedure was technically successful in all the10patients.At baseline,8of10(80%)of subjects in the surgical group had an abnormal pH study,and theTABLE II.Laryngoscopic Findings(Baseline,6and12Months Postoperative).Postfundoplication(%)Baseline6Month12Month Posterior cricoid wall erythema/edema40200 Posterior pharyngeal wall erythema20100 True/false vocal cord erythema/edema40100 Arytenoid complex erythema/edema502010 Medial arytenoid wall erythema/granularity603010 Postpharyngeal cobblestoning000 Redundant tissue/pseudosulcus2000 Interarytenoid bar erythema50100TABLE III.Median(Interquartile Range)Percent of Time pHϽ4.Percent pHϽ4Baseline4-month PostPPI Therapy3Month Postoperative12Month Postoperative ProximalTotal 2.3(0.05–8.5)0.00.0-Upright 2.6(0.1–11.7)0.00.0-Supine0.0(0–1.2)0.00.0-DistalTotal8.6(4.0–11.9)0.00.00.3(0.0–0.7) Upright10.3(3.6–13.7)0.00.00.1(0.0–0.4) Supine 6.4(0.3–13.15)0.00.00.0PPIϭproton-pump inhibitor.remaining2patients had evidence of reflux by barium esophagram.However,all these patients had normalized pH monitoring after4month PPI therapy.At3and12 months postfundoplication,the degree of esophageal acid exposure was significantly(PϽ.001)less than baseline values but similar(Pϭ1.0)to those obtained while on twice-daily PPIs(Table III).Manometric data revealed that none of these patients had abnormal manometry at3 months except“incomplete relaxation of the LES(lower esophageal sphincter),”which is a common finding post-fundoplication.Outcome at12MonthsAt1year follow-up,laryngeal symptoms improved in only1of10(10%)of these patients(Ͼ50%subjective improvement).Despite lack of improvement in laryngeal symptoms,heartburn resolved in all the patients.Inter-estingly,laryngeal signs improved in80%of patients.Five of10(50%)subjects were noted to have resolution of their initial findings at the6month postoperative follow-up.An additional3of10(30%)subjects were noted to have nor-malized laryngoscopic examinations at the12month follow-up visit.An additional two patients had improve-ment in laryngeal symptoms after treatment for asthma and allergies after the completion of the study period. DISCUSSIONThe results of this prospective study suggest that there is poor correlation between laryngeal signs and symptoms when monitoring therapeutic outcomes.Thus, although laryngeal signs resolved in80%of patients within a year after technically successful surgery,symp-tomatic improvement occurred in only10%of patients. Thus,neither signs nor symptoms may be used as a sur-rogate for the other.The results of this study confirm the findings of an earlier study conducted by Belafsky et al.11in which6 month follow-up was performed for LPR patients treatedAPPENDIX.Larynx/Pharynx Findings.Name:Clinic No:Date:Presence of the Following:Yes No Yes No1.Posterior Pharyngeal Wall 6.True Vocal Foldsa.Erythema a.Erythemab.Edema b.Edemac.Cobblestoning c.Surface Irregularityd.Mass Lesions(polyps)2.Interarytenoid Bar7.False Vocal Foldsa.Present a.Erythemab.Erythema b.Edemac.Blanched c.Surface Irregularityd.Irregular3.Posterior Commissure8.Anterior Commissurea.Erythema a.Erythemab.Edemac.Surface Irregularity4.Posterior Cricoid Wall9.Epiglottisa.Erythema a.Erythemab.Edema(laryngeal surface)c.Redundant Tissue b.Erythema(petiole)5.Arytenoid Complex10.Aryepiglottic Foldsa.Apex Erythema a.Erythemab.Apex Edema b.Edemac.Medial Wall Erythemad.Medial Wall Erosione.Medial Wall Granularitywith twice-daily PPIs.In that study,symptom improve-ment ceased at2months,whereas signs continued to improve over the6months.In our study,however,pa-tients who had good response to the twice-daily PPIs were excluded after4month therapy(65%),leaving only symp-tomatic nonresponders(35%)for the study.Thus,it ap-pears that if symptoms do not improve in2to4months after aggressive acid suppression,they are unlikely to improve even after a follow-up of more than a year despite having definitive therapy for reflux(fundoplication),and signs and symptoms continue to be dissociated from one another.Common throat symptoms attributed to LPR include hoarseness,vocal fatigue,chronic throat clearing,postna-sal drip,chronic cough,dysphagia,and globus.1,7How-ever,many of these symptoms are nonspecific and may be caused by other conditions such as smoking,allergies, postnasal drip,and neurogenic mechanisms.1But these symptoms are attributed to GERD on the basis of the findings of laryngoscopic examination in which the pres-ence of edema and erythema are considered synonymous with GERD.1,7,12In our study as well,these two signs were the most common(approximately60%)findings responsi-ble for LPR diagnosis.This also appears to be the most prevalent method of LPR diagnosis in many ENT prac-tices across the country,irrespective of teaching or non-teaching status.13For example,in a survey of approxi-mately2,000gastroenterologists and ENT physicians, Ahmed et al.13reported that edema and erythema of the larynx were the most common reasons for LPR diagnosis.However,the specificity of these findings for LPR diagnosis is questionable because an earlier study by Hicks et al.8found that up to87%of healthy volunteers had at least one sign attributed to LPR.In a more recent study,Milstein et al.9found a similarly high percentage of healthy population having laryngeal abnormalities.Fur-thermore,they also found that the use of different endo-scopic instruments resulted in significantly different la-ryngoscopic findings.Thus,flexible endoscopy found abnormalities in93%of the population compared with 83%through rigid endoscope.Rightfully,they questioned the utility of these findings to diagnose LPR given a low specificity and positive predictive value.There is also sig-nificant inter-and intra-observer variability in diagnosis of LPR.14,15Thus,presence of laryngeal signs cannot be taken as evidence of LPR,and more significantly,an LPR label should not be rigidly applied on patients,especially when they do not respond to aggressive acid suppressive therapy.The results of this study further suggests a possible multifactorial etiology for LPR,further supported by the fact that,in most of our patients,symptom improvement occurred only after adjunctive therapy for other condi-tions.Given the lack of specificity of any of the diagnostic tests in this patient group,empiric therapy with aggres-sive acid suppression with PPIs is often advocated as the initial test to determine whether GERD is the cause of patients’chronic symptoms.1,16Medical therapy in pa-tients with suspected LPR results in an overall response rate of50%to70%.1On the basis of the results of our study,it is unlikely that patients’chronic laryngeal symp-toms will improve postfundoplication,given their previous lack of response to aggressive PPI therapy.Our study is the first to prospectively evaluate the role of fundoplica-tion in patients with suspected LPR unresponsive to PPI therapy.However,prior observational studies have sug-gested similar outcome in patients with classic GERD or other atypical symptoms.17–23For example,So et al.,17 studying150consecutive patients after fundoplication, found that only56%of patients had relief of atypical symptoms,whereas typical heartburn symptoms resolved in93%.Furthermore,the only preoperative predictors of relief of atypical symptoms were prior clinical response to pharmacologic acid suppression and abnormal hypopha-ryngeal pH results.More specifically,a recent uncon-trolled case series20evaluating the outcome of patients with LPR reported84%symptom improvement postfun-doplication.However,this study again demonstrated a poor outcome in those previously unresponsive to PPI therapy.Therefore,on the basis of the results of these studies,continued symptoms on aggressive acid suppres-sion is most likely an indication for investigating other allergy,sinus,or pulmonary causes for patients’residual symptoms.The results of our study are strengthened by a pro-spective design,a long period of follow-up,and inclusion of only aggressive PPI therapy nonresponders.Blinded symptom assessment and laryngoscopic examinations documented changes in laryngeal symptoms and signs up to12months postoperatively.The main weakness of the study appears to be small sample size.However,given the significantly different improvement rates between signs and symptoms in these patients at1year(80%vs.10%),it has enough power(Ͼ95%)to suggest a lack of correlation between signs and symptoms at an alpha level of0.01. CONCLUSIONSThere appears to be poor correlation between laryn-geal signs and symptoms for the diagnosis of LPR,partic-ularly when monitoring therapeutic outcomes in patients unresponsive to PPI therapy.Patients who do not respond to twice-daily PPIs for4months are unlikely to respond to even more aggressive therapies such as fundoplication. Therefore,other etiologies for the symptoms should be actively sought in PPI unresponsive patients. 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