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  Reflux Laryngitis: An Update, 2009–2012 *Mary J. Hawkshaw, †Parmis Pebdani, and *Robert T. Sataloff,  *Philadelphia, Pennsylvania, and   y  Lancaster, California Summary: Purpose of Review.  The importance of laryngopharyngeal reflux (LPR) is acknowledged widely.However, controversy remains regarding pathophysiology, diagnosis, and treatment. This review addresses current lit-erature from late 2009 through the first half of 2012 and complements our previous review of literature from 2006through the middle of 2009. Both reviews highlight controversies and current research. RecentFindings.  Although controversies have not been resolved fully, additional research has expanded approachesto diagnosis and treatment of LPR. Recent studies shed additional light on pathophysiology. New imaging techniqueshave been introduced and they prove particularly useful in assessing LPR. Research has improved the understanding of the value of selected acid measurement techniques. The efficacy of treatment remains controversial. Summary.  LPR clearly is an important entity. However, disagreements persist regarding optimal diagnosis tech-niques, criteria of normalcy, and treatment efficacy. Additional studies are encouraged to further our understandingof pathophysiology, diagnosis, treatment, and the long-term effects of LPR and LPR treatment. Key Words:  Laryngopharyngeal reflux–Gastroesophageal reflux disease–Proton pump inhibitor therapy–Acidsuppression therapy–24-Hour pH impedance testing–Restech–Pharyngeal acid measurement. INTRODUCTION Laryngopharyngeal reflux (LPR), an extraesophageal variant of gastroesophagealreflux disease (GERD) isone of the mostcom-mon conditions in otolaryngologic practice. Interest in LPR hasgrown substantially over the past two decades. However, contro-versy persists regarding the accuracy of diagnosis of LPR, itspathophysiology,andtheefficacyoftreatment.Thereisapaucityof definitive, prospective, and evidence-based studies to supportcurrent clinical management of LPR, which has been acceptedwidely on the basis of clinical experience. Our review in 2009of the published literature on LPR identified trends and contro-versies in the diagnosis and treatment of LPR. 1 Much informa-tion has developed since the time of that publication, and webelieve that the more current literature is of value to clinicians.Inthisreview, weexaminethedatapublished from2009throughJune 2012 and their impact on clinical practice. PATHOPHYSIOLOGY LPR is believed to be caused by retrograde flow of gastric con-tents (particularly acid and pepsin) that affect pharyngeal andlaryngeal mucosa by direct contact or by a secondary mecha-nism. 2 For example, acid irritation of the distal esophagus cancause chronic throat clearing and cough mediated by the vagusnerve that also can damage laryngeal mucosa. 3,4 Reflux of  bilesalts can cause irritation of the laryngeal mucosa, as well. 5,6 Animal studies have shown that acid combined with pepsin(acid-activated enzyme) compromises the integrity of the vocalfold epithelium. In 2010, Habesoglu et al 7 reported that rats ex-posed to an acidic pH in the presence of pepsin developededema of the lamina propria, submucous gland hyperplasia, andmuscular atrophy. Erickson and Sivasankar 8 reported that the ep-ithelial barrier resistance of the vocal fold is compromised whenexposed to acid and pepsin. They described transepithelial resis-tanceasamarkerofepithelialbarrierresistancethatmeasurestheability to restrict movement of solute and solvents. The authorspointed out that less than three episodes of reflux per week caninjure vocal fold mucosa, in contrast to 0–50 reflux events dailythat are considered normal exposure in the distal esophagus.In 2009, Johnston et al 9 reported that pepsin invades thelaryngeal epithelial cells by receptor-mediated endocytosisand that pepsin activity is maximal at a pH of 2.0. Bulmeret al 10 showed that the effects of acid and pepsin exposure onporcine laryngeal mucosa were similar to the effects observedin the human larynx in patients diagnosed with LPR. Samuelsand Johnston 11 reported that the presence of pepsin in the air-way indicates reflux. However, they reported that there areonly two methods used to identify pepsin in the airways, immu-nologic and enzymatic, both of which have advantages and dis-advantages. Richter 12 stated that gastric acid combined withpepsin and bile salts is known to be causally related to the de-velopment of chronic esophagitis and Barrett esophagus. Incontrast, they reported that weak or nonacid refluxate has notbeen shown to cause damage to the esophageal or extraesopha-geal structures including the larynx and the lungs.Chong and Jalihal 13 reported a greater percentage of LPRsymptoms in patients with heterotropic gastric mucosal patch(HGMP) of the distal esophagus. HGMP is ectopic gastric mu-cosa typically observeddistal to the upper esophageal sphincter(UES) and thought to be congenital. Due to the fact that HGMPcan produce acid, the authors suggest that this may be the etiol-ogyofLPRinsomepatients.Infact,intheirstudy,patientswithHGMPexperiencedLPRsymptoms toagreaterdegree(73.1%)as compared with their non-HGMP patients (25.9%). Basseriet al 14,15 reported that the endoscopic prevalence of HGMP islow, ranging from 0.1% to 10% in reported patients rangingin age from 16 to 75 years. Typical symptoms in patientswith HGMP include dysphagia, globus pharyngeus, cough,hoarseness, and shortness of breath. They reported that theHGMP is a source of acid production. This observation hasbeen supported by pH monitor studies showing acid in this Accepted for publication March 7, 2013.From the *Department of Otolaryngology-Head and Neck Surgery, Drexel UniversityCollege of Medicine, Philadelphia, Pennsylvania; and the  y Kaiser Permanente-Lancaster,Lancaster, California.Address correspondence and reprint requests to Robert T. Sataloff, Department of Otolaryngology-Head and Neck Surgery, Drexel University College of Medicine, 1721Pine Street, Philadelphia, PA 19103. E-mail: RTSataloff@PhillyENT.comJournal of Voice, Vol. 27, No. 4, pp. 486-4940892-1997/$36.00  2013 The Voice Foundationhttp://dx.doi.org/10.1016/j.jvoice.2013.03.001  area. Parietal cells with oxyntic mucosa are the most commonhistologic type reported.Histopathologicinflammationanditsassociationwiththepath-ogenesis of esophageal and extraesophageal disease has been thesubject of ongoing research. Wada et al 16 evaluated histopatho-logic inflammation of the upper esophagus in comparison withthe lower esophagus. When compared with their control group,they found inflammation of the upper esophagus to be signifi-cantlygreaterinpatientswithabnormallaryngopharyngealsymp-toms and significantly greater lower esophageal inflammatoryhistopathologyinpatientswithclassicrefluxsymptoms(GERD).Park et al 17 used transmission electron microscopy to exam-ine cellular damage of the esophageal epithelium by gastric re-fluxate. They measured the intracellular space (IS) andquantified the dilatation of the intracellular space (DIS). Theycompared two groups: patients who had LPR without GERDand a second group had LPR with GERD. They reported thatthe IS of the esophageal epithelium was significantly more di-lated in the LPR with GERD group. Amin et al 18 reportedthat DIS of esophageal epithelium is considered a specificmarker in GERD. They studied a group of patients with LPRand sore throat in whom they found DIS in oropharyngealbiopsy specimens. They also found dilatation of IS in the laryn-geal mucosa in animal models exposed to pepsin.Vardouniotis et al 19 reported that a hypotensive lower esoph-ageal sphincter (LES) is a significant pathophysiological com-ponent of LPR, noting that complex molecular mechanismsinvolved in the function of the LES and genetic factors are in-volved in tissue protection from reflux. They reported that,compared with the esophagus, laryngeal and pharyngeal mu-cosa is more susceptible to tissue damage from refluxate be-cause the larynx is not protected by peristalsis nor bufferedby salivary bicarbonate. They reported that transforminggrowth factor beta-1, which inhibits inflammatory response,hasshowngeneoverexpression inpostcricoid fibroblastsand fi-broblast growth factor 2 has shown decreased expression.Cheng et al 20 suggested that the macrophage activation causedby gastric acid exposure should be considered also in the path-ogenesis of GERD and aspiration-induced lung disease.In2010,basedontheir research,Szczesniaketal 21 suggestedupregulationoftheesophago-UESrelaxation responseasapos-sible mechanism in the pathophysiology of reflux laryngitis.They found that the UES relaxation reflex induced by rapidair insufflation of the esophagus is upregulated in patientswith posterior laryngitis when compared with healthy controls.They also found that this group of patients had a higherpharyngo-UES contractile reflexthreshold, which is considereda mechanism of airway protection.Recent studies indicate that many questions regarding thepathophysiology of the LPR and other extraesophageal mani-festations of GERD in LPR remain unanswered and substantialadditional research is needed. DIAGNOSIS Kotby et al 22 pointed out that the nonspecific clinical manifes-tations ofLPR may be caused by other conditions and that thereis a lack of well-controlled studies to assess response to treat-ment. We concur with their observations. Ayazi et al 23 reportedthat meta-analysis of studies on the effects of proton pump in-hibitor (PPI) therapy on controlling the symptoms of LPR hassuggested that only 50% of this patient population reports im-provement in symptoms. However, we caution that intrinsicweakness in the studies included in meta-analysis raise con-cerns about the validity of the data. The authors proposeda new paradigm for diagnosing LPR based on loss of alkaliza-tion in the cervical esophagus. In their patients with LPR, theyobserved a failure to maintain a neutral pH in the cervicalesophagus based on increased exposure to pH less than 4 anddecreased exposure to a pH greater than or equal to 7, as com-paredwithnormal patients.The authorssuggested thatsensitiv-ity for detecting abnormal reflux and its causal relationship tolaryngopharyngeal symptoms is increased by consideringboth the percent time recorded of pH less than 4 and the percenttime with pH greater than or equal to 7. They believe that loss(inabilitytomaintain)ofanalkaline(pHgreaterthanorequalto7) environment in the cervical esophagus is an indicator of de-creased ability to protect tissues from damage, in contrast to in-creased measurement of pH less than 4, which has beenaccepted as causing pathologic changes associated with LPRsymptomatology. Chong 24,25 suggested that the cervical inletpatch (CIP) of the esophagus can be an etiology of LPR, butoften it is unrecognized during endoscopy and subsequentlyunderdiagnosed. The authors reported that the incidence of CIP ranges from 0.29% to 10% in endoscopic examinations.Twenty-four-hour pH monitoring is the most important diag-nostic tool for quantifying esophageal reflux in patients withsymptoms of GERD. Originally, the ambulatory pH monitoringsystems used a single-probe catheter, placed 5 cm above theLES. This system did not provide information regarding prox-imal esophageal acid exposure, an area thought to correlate thedevelopment of extraesophageal manifestations of GERD in-cluding LPR. Multiple advances in technology have occurred.Double-probe (esophageal and hypopharyngeal) 24-hour pHmonitoring used to be regarded as the ‘‘gold standard’’ for diag-nosis of LPR and still is by some clinicians. However, consen-sus has not been reached on the placement of the probe, thenumber of sensors required, or on the interpretation of results.Muderrisetal 26 suggestedthatatriplesensorpHcathetercanidentify accurately episodes of hypopharyngeal reflux when theproximal probe is placed in the pharynx and not in the upperesophagus. However, the accuracy of standard esophagealprobes when placed in the pharynx has been challenged. Golubet al 27 studied 15 patients with LPR symptoms by placing si-multaneouslyastandarddualpHprobeandtheRestechoropha-ryngeal probe (Respiratory Technology Corporation, SanDiego, CA). The Restech oropharyngeal probe measures pHand liquid or aerosolized droplets, which is different from stan-dard pH probes that require a liquid environment for properfunctioning. Their data showed that the oropharyngeal probecorrelated closely with the sensor near the UES when calculat-ing percentage of time of acid exposure. Wiener et al 28 com-pared the Restech oropharyngeal probe to three traditional pHprobes (two esophageal and one pharyngeal) on 15 patients Mary J. Hawkshaw,  et al   An Update of Laryngopharyngeal Reflux  487  with LPR symptoms. They reported that the Restech probe wassensitive in detecting pH events that srcinated in the distalesophagus and migrated toward the oropharynx. They reportedalso that the traditional criterion of pH less than 4 as an indica-tor of LPR might not be useful in the oropharynx. The authorssuggested that a ‘‘significant pH event’’ might be redefined asa drop of greater than 3.5 standard deviations from baselinepH. Sun et al 29 described their experience using the Restechsystem reporting that it proved sensitive for the detection of acid reflux, was minimally invasive, and was tolerated wellby patients.Sato et al 30 described their experience using a tetra-probe,24-hour pH monitoring system. The proximal probe is placedin the hypopharynx; a second probe is placed in the mid-esophagus; the third probe is placed a few centimeters abovethe LES (but not specifically 5 cm); and the distal sensor isplaced in the stomach. This system is advantageous in that itmeasures pH simultaneously at all four sites, providing infor-mation regarding the relationship of these values. However, inour opinion, there are significant disadvantages associatedwith failure to have a sensor 5 cm above the LES, a standardsite that permits comparison with other literature. In a separatereport, the authors described their results using the tetra-probe,24-hour pH monitoring system to evaluate patterns of LPR andGERD and to determine the validity of using pH 5.0 as an indi-cator of LPR. The data suggest that pH levels less than 4 andless than 5 are indicative of significant LPR events. 31 An inter-esting study was reported in 2010 by Zelenik et al. 32 They per-formed a prospective dual-probe pH monitoring study in 46patients with complaints of globus pharyngeus for more than3 months. They collected data using a pH less than 4 and a sec-ond data group using both pH less than 4 and less than 5. Extra-esophagealreflux wasfoundin23.9% oftheir patients usingpHlessthan4.0analysis.When datawerecalculatedusingbothpHless than 4 and less than 5, they found extraesophageal reflux inan additional four (8.7%) patients whose reflux had not beendetected when pH 4 alone was used.Combined multichannel intraluminal impedance and pH(MII/pH) monitoring is a newer technique now being usedmore widely in the diagnosis of LPR and currently consideredthe gold standard rather than older dual-probe monitoring tech-nology. Combined MII/pH monitoring identifies reflux epi-sodes in liquid, gas, or mixed forms, which enable thedetection of both acid and nonacid reflux. Wu 33 reported thatcombining MII and dual-channel pH monitoring increases thediagnostic yield by approximately 10% when compared withcombined MII and single-channel pH monitoring systems.Lee et al 34 reported a two-fold increase in diagnosing refluxin patients with LPR symptoms, using combined dual-channelimpedance/pH-metry.Lootsetal 35 reportedthatthead-dition of MII to standard pH monitoring increases the yield of symptom association in children and infants with confirmedreflux.Researchers and clinicians have developed additional objec-tive and subjective tools to aid in the diagnosis of LPR and toassess outcomes of treatment. As described previously, theReflux Symptom Index (RSI) 36 was designed to measure theseverity of laryngeal symptoms and the Reflux Finding Score(RFS) 37 is used to grade findings on laryngoscopy. More re-cently, the Pharyngeal Reflux Symptom Questionnaire wasdeveloped by Andersson et al. 38 It is a self-administered ques-tionnaire specific for LPR patients. They compared this tool tothe LPR-HRQL (health related quality of life) and the RSIand reported strong correlation. The authors also reported thatthe questionnaire discriminated between patients without andwith LPR. Several reports 39,40 have suggested that anxiety,depression, and depressive symptoms can impact subjectiveresponses to quality-of-life tools and symptom indices andthus diminish the predictive value of symptom assessment,which raises concern about the usefulness of these tools. Re-searchers in China 41 reported significantly higher VH1 scoresand higher depression scores in their patients with LPR.Nishimura et al 42 evaluated postoperative LPR in patientswho had undergone surgery for esophageal cancer. They pro-posed a classification system for grading findings on endoscopyto facilitate more accurate diagnosis of LPR in this patient pop-ulation. Katsinelos et al 43 reported that the laryngopharynx isnot examined routinely during esophagogastroduodenoscopy(EGD). Their prospective study found significant laryngeal pa-thology including leukoplakia, Reinke edema, and posteriorlaryngitis in their patients, and they recommended screeningexaminations of the laryngopharynx during all EGDprocedures.Dale etal 44 suggestedthat endoscopiclaryngealsensorytest-ing provides valuable, quantifiable assessment of the degree of sensory impairment needed to stimulate the laryngeal adductorreflex in patients with LPR. We have found sensory testing use-ful; but the equipment to perform quantified laryngeal sensorytesting is no longer available commercially.Eller et al 45 compared the fiberoptic and distal chip technolo-gies using flexible laryngoscopy for recognizing laryngeal find-ings associated with LPR. Three senior otolaryngologists andtwo resident/fellow otolaryngologistswere asked to grade phys-icalfindingsof LPRontheimagestheyevaluated using both theRFS and a posterior erythema grading tool developed by the au-thors for this project. They compared the findings with these en-doscopy systems to those from the images obtained with a rigidlaryngeal telescope. The authors found that the fiberoptic anddistal chip technologies were almost identical in their abilityto detect LPR. However, both flexible technologies were foundto be significantly less sensitive than a rigid laryngeal telescopicexamination for diagnosing LPR. Other researchers have re-ported significant LPR symptoms including dysphonia associ-ated with endoscopic evidence of esophagitis. 46,47 DiagnosticproceduresincludingpHmonitoring,manometry,impedance manometry, and flexible endoscopy have all ad-vanced the diagnosis and management of patients with GERDand LPR. Since the introduction of the flexible nasopharyngo-laryngoscope, research and development have focused on im-proving image quality through changes in illumination,resolution, and magnification of images. New technology hasbeen applied to video-endoscopic systems including narrowband imaging, iScan technology, and auto-fluorescent imag-ing. 48–56 High-speed optical coherence tomography can image Journal of Voice, Vol. 27, No. 4, 2013 488  cross sections of soft tissue, and spectrally encoded confocalendomicroscopy provides images with subcellular resolu-tion. 57–60 These technologies have shown great promise foradvancing mucosal imaging and potentially early detection of pathology. MEDICAL TREATMENT Medical treatment of LPR has been based on the principles of the treatment of GERD (heartburn and erosive esophagitis)and clinical experience. The diagnosis and treatment of LPRremain controversial in otolaryngologic practice. Well-controlled, prospective, evidence-based studies without signif-icant flaws are scarce.LPR and GERD are chronic conditions that may involvelong-term medical management. Education is essential to pro-mote patients’ compliance with their long-term care regimens.Treatment involves a combination of lifestyle modifications,pharmacotherapy, andantireflux surgerywhen indicated. Treat-ment focuses on elimination of symptoms, healing of mucosa,managing complications secondary to GERD and LPR, andsurveillance of patients once they become asymptomatic.Lifestyle modifications can be simple and effective in im-proving symptoms for some patients. Head of bed elevationand dietary modifications (decreased intake of gastric irritantssuch as acidic foods and fatty foods) help reduce symptoms.Koufman 61 evaluated the clinical impact of a low-acid diet onthetherapeuticoutcomeinpatients treatedforLPR.Shestudieda group of 20 patients with persistent signs and symptoms of LPR despite twice daily use of PPI and an H2 blocker at bed-time. The low-acid diet described by Dr. Koufman was definedby eliminating all foods and beverages with a pH less than 5.Thepatientswereplaced onthisdietforaminimum of2weeks,and both the RSI and RFS were determined before and after thediet. The findings of Koufman show that both the clinical signsand symptoms in these patients, with persistent symptomsdespite PPI treatment, improved following an acid-free diet.Elimination of symptoms caused by LPR requires control of gastricacidsecretioninmostpatientsinwhomrefluxisnotcon-trolled mechanically (such as through surgery). Research andclinical experience have shown that patients with LPR often re-quire high-dose medications including H2 receptor antagonistsandprotonpumpinhibitors.TheH2blockersinhibitgastricacidsecretion.Protonpump inhibitorsblocktheH+/K+ATPenzymethat catalyzes the terminal step in acid secretion in the parietalcells.As Altman and Radosevich 62 pointed out, although H2 re-ceptor blockers are still used, PPI therapy is the most effectiveandmostwidelyusednonsurgicaltreatmentforthetreatmentof GERD and LPR. BruleydesVarannesetal 63 reportedthat PPIs’superiority over other drugs has been well established for bothshort- and long-term treatment of GERD. Patients with erosiveesophagitis are more responsive to PPIs than patients with non-erosive reflux disease. PPIs also have become widely used andproven to be safe and effective in the management of GERD inchildren, although to date, only omeprazole, lansoprazole, andesomeprazole are approved for use in children. 64,65 A randomized, placebo-controlled study revealed improvedLPR symptoms compared with placebo after 12 weeks of treat-ment with rabeprazole 20 mg twice daily. 66 These authors re-ported a relapse of symptoms 6 weeks after stopping PPItherapy, suggesting that LPR requires longer duration of treat-ment. Many clinicians still advocate the use of empiric therapywithtwicedailyPPIdosingfor6–12weeks(onaverage)asadi-agnostic tool in patients with suspected LPR. 67,68 However, webelieve that this is not an adequate approach especially fornonresponders, as some patients may produce acid even whentaking two or more PPIs daily. pH monitoring on medicationsis invaluable in detecting these patients; and for manypatients, PPI treatment must be continued indefinitely.Dadabhai et al 69 reported that rabeprazole has a faster onsetof action in comparison with other proton pump inhibitors.They cited rabeprazole’s high pKa of 5.0, which facilitates ac-tivation at a higher pH, as a possible reason for its faster onset.Theydescribedrabeprazole’spathway ofmetabolism asnonen-zymatic, thus making it less affected by the genetic polymor-phisms of the CYP2C19 on which the other PPIs depend.In 2010, Fass et al 70 reported the results of a randomized,placebo-controlled study that evaluated the effectiveness of esomeprazole twice daily in their patients with LPR, all of whom had undergone endoscopy and pH monitor testing. Fol-lowing the 3-month trial, the results revealed no significant dif-ferencesinvideostroboscopicRFSandnosignificantdifferencein acoustic measures after treatment, comparing the esomepra-zole group and the placebo group. The patients completeda voice use and quality diary and a symptom diary before treat-ment and at the end of a 3-month study, and no significant dif-ferences were found in these between the two groups.Youssef and Ahmed 71 reported that 57% of their 212 patientsdiagnosed with LPR tested positive for the  Helicobacter pylori stool antigen (HPSA). HPSA-negative patients were treatedwith esomeprazole alone and 96.6% improved. HPSA-positivepatients were divided into two groups. Only 40% of thosetreated with esomeprazole alone improved, whereas 90% of those who received triple therapy (esomeprazole, amoxicillin,and clarithromycin) showed improvement. These findings sug-gest that screening and treatment for HPSA may be advisable inLPR patients, although attention to  H. pylori  is not routine inmost centers.Chapman et al 72 reviewed the adverse effects and possiblecomplications of long-term PPI use. They cited recent reportsthat have shown an association between long-term PPI useand altered absorption of minerals and vitamins, orthopedic in- jury, acute coronary syndromes, and increased risk for infec-tions. The authors recommend caution when usingomeprazole in patients with acute coronary syndromes and car-diology consultation when considering PPI use in patients tak-ing clopidogrel.Reimer et al 73 described symptom-producing rebound acidhypersecretion (RAHS) following withdrawal of PPI therapyafter 2 months. Acid-related symptoms occurred in a group of healthy volunteers after treatment was stopped, which the au-thors interpreted as suggesting that RAHS may result in PPIdependency. Mary J. Hawkshaw,  et al   An Update of Laryngopharyngeal Reflux  489
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