Reflux Laryngitis: an Otolaryngologist's Perspective

Controversies in Gastroenterology Reflux laryngitis: an Otolaryngologist’s perspective

Luis Humberto Jiménez Fandiño, MD,1 Natalia Mantilla Tarazona, MD,2 Javier Andrés Ospina Díaz, MD.3

1 Otolaryngologist and Maxillofacial Surgeon. Director Abstract of Laryngology and Pathology in the Voice Section of the Otolaryngology Unit at the Hospital Universitario Refl ux laryngitis is recognized as an extra-digestive manifestation of gastroesophageal refl ux. It has beco- San Ignacio, Pontificia Universidad Javeriana. me one of the most frequent reasons patients consult with otolaryngologists. In this review we present the Bogotá, Colombia [email protected] otolaryngologist’s point of view on this disease, and discuss the continuing controversy about its pathophysio- 2 Otolaryngologist. Pontificia Universidad Javeriana. Bogotá, Colombia logy, diagnosis and treatment. 3 Otolaryngologist. Pontificia Universidad Javeriana. Bogotá, Colombia Key words Translated by T.A. Zuur and The Language Workshop Laryngitis, gastroesophageal refl ux disease (GERD), laryngopharyngeal refl ux.

...... Received: 29-03-11 Accepted: 02-08-11

INTRODUCTION middle ear and the adenoids of patients with otitis media with eff usion (OME). It is believed that the pepsin reaches Refl ux laryngitis, also known as laryngopharyngeal refl ux the middle ear in gastric content that ascends through the (LPR), is one of the extra-digestive manifestations of gas- nasopharynx and the eustachian tube. Th is establishes an troesophageal refl ux disease (GERD) that is produced by the important association between OME’s pathogenesis and retrograde fl ow of the gastric contents (acid, pepsin) or duo- chronic otitis media (6-8). denal contents (biliary salts, pancreatic enzymes) toward the Although data about the relation of gastric refl ux and larynx and the pharynx (1). Although GERD and LPR are extra-digestive laryngeal manifestations has been published considered to be part of a spectrum within one disease with a in the literature of otolaryngology for at least four decades multifactorial etiology, they diff er in their symptoms, clinical (9), it was fi rst named LPR by Koufman at the beginning manifestations and responses to treatment. of the 1990’s (10). Since then this entity has been diagno- Gastric content refl ux can aff ect organs and systems in the sed more and more frequently by otolaryngologists, to the vicinity of the digestive system as proven by descriptions of point that it is over-diagnosed. From 1990 to 2001in the a strong association between refl ux tide and various infl a- United States, the number of visits to doctors, especially to mmatory pathologies of the head and neck. Th ese include otolaryngologists, for diseases related to gastroesophageal chronic rhinosinusitis, allergic rhinitis, recurrent tonsillitis, refl ux increased 306%. Prescription of pump proton inhibi- hypertrophy of the tonsils and adenoids, obstructive sleep tors (PPI) increased 14 times (11). apnea-hypopnea syndrome (OSAHS), asthma, bronchiec- In this article we will review current concepts of LPR, pre- stasis, pneumonia, chronic cough, dysphagia, laryngomala- sent controversies about the reality of its existence and its cia, pharyngitis, tracheitis, and subglotic stenosis (2-5). diagnosis and treatment, and discuss the otolaryngologist’s Th ere have even been fi ndings of high levels of pepsin in the role in the handling of these patients.

193 © 2011 Asociaciones Colombianas de Gastroenterología, Endoscopia digestiva, Coloproctología y Hepatología EPIDEMIOLOGY AND PHYSIOPATHOLOGY of the distal esophagus which produces coughing, throat clearing and laryngospasms (13,18). Th e erratic form of presentation of this disease combined with the current absence of a highly sensitive and specifi c EFFECTS ON THE LARYNX diagnostic method for diagnosing GERD and LPR makes it impossible to determine the real impact and association Th e epithelium of the vocal folds is squamous, cylindrical of these pathologies. and stratifi ed. Connections by complexes of apical unions For otolaryngologists, LPR and GERD play an increasin- create a barrier mechanism against external and internal gly important role. Th e evidence shows a signifi cant increase att acking agents including LPR (19). in diagnoses and treatment of refl ux related diseases (11). In order to evaluate these barrier mechanisms of the epi- In the United States the direct cost of antirefl ux treatment thelium, we have used transepithelial electrical resistance (especially PPIs) is esteemed at more than 14 trillion dollars (TER) as an epithelial marker in the larynx and esophagus. per year. Th is does not include the costs of medical appo- TER measures the capacity of the tissue to act as a barrier by intments, diagnostic tests or indirect costs related to eff ects restricting the movement of solutes and solvents through on labor productivity and quality of life (12). the paracellular or transcellular route. Experimental studies Some studies show that up to 10% of the patients who have found that exposure of healthy vocal folds to acid and go to an otolaryngologist present symptoms related to LPR pepsin diminishes TER, thereby increasing the permeabi- and that approximately 50% of patients with dysphonia lity of the epithelium and making it more susceptible to have signs of underlying refl ux disease (10,11). injury (19). Currently, we do not have suffi cient evidence about the Other studies have demonstrated increased paracellular relation between GERD and LPR. Th is is partly due to spaces in patients with LPR (20) and a noticeable diminu- the fact that patients with LPR who have otolaryngologi- tion of E-Cadherin (transmembrane surface molecules that cal symptoms do not present common symptoms related play a very important role in adhesion) in 37% of patients to GERD such as epigastralgia and regurgitation (13). In with LPR (21,22). addition, patients who have the most important symptoms In addition, it has been found that patients with LPR of GERD are not usually tested for extra-digestive manifes- have intracellular depletion of carbonic anhydrase III in tations. For these reasons it is believed that the prevalence the presence of pepsin. Carbonic anhydrase III is produ- of LPR in the population of patients with GERD has been ced to stabilize cellular pH when the cell comes in contact underestimated (14). with acid. It does so by generating a bicarbonate barrier. A study in which 1,383 patients with GERD were inter- Diminution of carbonic anhydrase III results in a decrease viewed determined that LPR increases as the severity of in the protective response of the laryngeal tissue which is refl ux increases (14) while nothera study has demonstrated believed to play a very important role in alteration of the that 24% of patients with refl ux esophagitis had LPR (15). intercellular barrier associated with down-regulation of A third study included patients with chronic laryngitis that E-cadherin (22). It has also been found that that the Sep70 were divided into one group with GERD and one without epithelial stress protein in squamous tissue, which provides GERD. Aft er both groups had been treated with PPIs it epithelial protection, is also diminished in these patients was found that laryngeal symptoms and signs of laryngitis (23). signifi cantly improved only in the group with GERD (16). A study by Aviv et al. has shown that another mechanism LPR is a disease which has multi-factorial etiology that seems to infl uence alterations in protection of the in which determinant factors intervene. Th ese factors larynx is decreased sensitivity of the glott is caused by expo- include the functioning of the esophageal sphincters sure to gastric content. Th is study found that LPR patients (lower esophageal sphincter in GERD and upper esopha- had decreased laryngeal adductory refl exes in response to geal sphincter in LPR), tissue sensitivity and exposure administration of air pulses (24). time to gastric content (1, 17). It is important to note that experimental clinical studies Th e larynx is at high risk from contact with the contents and animal studies have demonstrated that the larynx is of the esophagus due to its near proximity to the digestive more susceptible to injury from exposure to gastric con- system. Th is is why it is logical to think that any refl ux which tents than is the esophageal tissue. One study has demons- passes above the upper esophageal sphincter can also aff ect trated that only 3 episodes of LPR per week, with pH less the larynx. Even so, another mechanism has been described than four, are required to produce changes in the laryngeal through which refl ux produces laryngeal lesions without tissue while at least 50 episodes per week of GERD are the necessity of direct contact with the larynx. It is the required to produce some degree of injury in the esophagus production of a vagal refl ex produced by the acidifi cation (22,25).

194 Rev Col Gastroenterol / 26 (3) 2011 Controversies in Gastroenterology In summary, all of these alterations in the cellular barrier As we can see, dysphonia is one of the main symptoms of and protective mechanisms of the larynx cause diminished LPR which is found in up to 50% of patients with voice alte- epithelial resistance and increased susceptibility to future rations and/or laryngeal pathologies (36). Nevertheless, in exposures to gastric content. children the clinical manifestations of this disease can be Th ese epithelial alterations are believed to produce diff erent from those in adults. Children can present recu- structural alterations in the larynx making refl ux laryngitis, rrent episodes of tonsillitis, laryngitis and tracheitis, which with or without granuloma formation, the main clinical occur as a consequence of abnormal exposition to acid in manifestation of LPR. LPR has also been identifi ed as the the upper respiratory tract. In these cases the presence of main cause of various other laryngeal pathologies including an acid pH generates infl ammation which favors changes in laryngeal stenosis, laryngeal nodules, polypoid degenera- the bacterial fl ora and recurrent infectious processes (37). tion, laryngomalacia, laryngospasm and paradoxical movement of vocal folds (1,26,27,28,29). REFLUX SYMPTOMS INDEX Refl ux is also believed to be a factor which negatively aff ects healing of vocal folds, adversely aff ecting the results Indexes found in the literature can help us quantify refl ux of laryngeal surgery. Two experimental studies on rabbits symptoms. Among them is the RSI (Refl ux Symptoms suggest that acid and pepsin signifi cantly aff ect the healing Index). Th is is a chart with nine questions which aim to of vocal folds (30) and that the healing of subglott ic tissue determine the severity of the symptoms related to LPR. is adversely aff ected by moderately acidic conditions (31). Th is patient must fi ll out this questionnaire at the time of Another study of 112 patients with LPR who underwent diagnosis and aft er treatment. Answers to questions are laryngeal surgery to treat Reinke’s edema, vocal polyps rankings from 0 to 5. Zero indicates “no problem”, and fi ve or nodules was conducted by Kantas et al. Two groups indicates “very troublesome.” Since some degree of refl ux is were randomly selected: one received PPIs prior to and found in normal patients, an RSI greater than 13 is conside- following surgery, the other group did not receive PPIs. Th e red to be abnormal (38) (Table 1). study found that LPR negatively aff ected re-epithelization and increased the recurrence of laryngeal injuries (32). Table 1. Refl ux Symptoms Index (RSI).

SYMPTOMS AND CLINICAL MANIFESTATIONS OF During the last month how did the following problems affect you: LARYNGOPHARINGEAL REFLUX 1. Hoarseness or a problem with your voice. 012345 2. Clearing your throat. 012345 An excellent clinical history is indispensable for identifi ca- 3. Excess throat mucus or postnasal drip. 012345 tion of this pathology. Th e patient should be asked about 4. Difﬁ culty swallowing food, liquids, or pills 012345 common refl ux symptoms and symptoms related to head 5. Coughing after you ate or after lying down. 012345 and neck pathologies, although it should be kept in mind 6. Breathing difﬁ culties or choking episodes 012345 the absence of these symptoms does not rule out this 7. Troublesome or annoying cough. 012345 disease. 8. Sensations of something sticking in your 012345 It is important to note that patients with LPR do not throat or a lump in your throat. usually present classic clinical GERD manifestations as 9. Heartburn, chest pain, indigestion or 012345 it has been demonstrated that many LPR patients do not stomach acid coming up have associated esophagitis or epigastralgia. Several studies have determined that LPR patients have an incidence of 0= no problem, 5= severe problem/ very troublesome. Adapted from epigastralgia of less than 40% and an incidence of esopha- Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the refl ux symptom index (RSI). J Voice 2002; 16: 274-77. gitis of less than 25% (1,10,33,34). Among the clinical manifestations of LPR are found a A study conducted by Belafsky et al. to validate the RSI great variety of signs and symptoms of otolaryngeal disea- scale evaluated 25 patients with LPR. Each patient’s pH was ses including dysphonia (71%), dry coughing (51%), throat monitored every 24 hours. Prior to beginning treatment, clearing (42%), globus pharyngis (47%) and hypopharyn- each patient completed the RSI twice: at the time of the fi rst geal secretions. We also fi nd dysphagia (35%), sensations consultation and 8 days aft er. Th e patient answered the RSI of post-nasal drip (PND), bitt er saliva, odynophagia and questionnaire again aft er 6 months of treatment including laryngeal spasms. In some cases coughing can become twice daily doses of PPIs and other anti-refl ux measures. eTh chronic with incapacitating coughing fi ts which wake the study found high reproducibility of pretreatment RSI results: patient during the night (35). 19.9 for the fi rst RSI and 20.9 for the second (p <0.001).

Reflux laryngitis: an Otolaryngologist’s perspective 195 Th e study included a control group of 25 additional patients of the same ages and genders as the LPR group who were found by using a database of patients who showed no evidence of LPR. Th e average pre-treatment RSI score for patients with LPR was signifi cantly higher than that of controls (21.2 versus 11.6 p < 0.001). Aft er six months of treatment the LPR groups average score dropped to 12.8, statistically similar to that of the asymptomatic group. Control group patients received no treatment since they were asymptomatic (38).

DIAGNOSIS

Th e basis for diagnosing this pathology is a combination of chronic or intermitt ent symptoms correlated with positive fi ndings in the larynx. A complete clinical history with an exhaustive otolaryngological physical examination is necessary for identifi cation of this disease. eTh physical examination must consider changes in the oral mucosa, hyperemia of the posterior pharyngeal wall, and lingual Figure 1. Telelaryngoscopy image of a patient with LPR symptoms tonsils, whether or not patient’s tongue is white, and laryn- showing increased and thickened secretions in the glott is with a geal changes seen with indirect laryngoscopy (37). heightened vascular patt ern. Th e diagnostic algorithm that we currently use is to fi rst identify symptoms suggestive of gastric refl ux with extra- digestive manifestations, and then identify whether or not there are structural changes in the larynx or neighboring tissues. To make this identifi cation we use a fl exible Fiber Nasolaryngoscope, fl exible Tele-laryngoscope and/or a laryngeal videostroboscope. Th e laryngeal videostroboscopy is a test that uses a strobe light which is synchronized closely to the frequency of vibration of the vocal folds. Th is allows us to appreciate what appear to be movements in slow motion of the process of vibration of the vocal folds. Th is examination is especially useful for identifying the alterations in the vibration patt ern of the folds that produce laryngeal lesions. Videolaryngoscopy and the laryngeal stroboscopy fi n- dings suggest LPR included pseudosulcus, thick secretions in the glott is, (Figure 1), irregular free edges, erythema and interarytenoid mucosal edema (Figure 2), posterior injuries such as ulcers and granuloma (65-74%) (Figure 3A and 3B), glott al and subglott ic stenoses, and paradoxical movement of vocal folds (39,40). 90% of patients with LPR are found to have pseudosulcus and these patients are 2.5 more likely to have positive pH measurements (70% Figure 2. Telelaryngoscopy image of a patient with LPR symptoms showing noticeable edema of the free edge of the vocal folds with heightened vascular sensitivity, 77% specifi city). patt ern as well as interarytenoid mucosa edema and erythema. A study which interviewed 2,000 otolaryngologists revea- led that the clinical signs most commonly used to diagnose An additional problem for diagnostic exactitude is the refl ux laryngitis are laryngeal erythema and edema (41). variability of diagnoses of extra-digestive refl ux manifesta- Nevertheless, these signs are not very specifi c, and it has tions from one observer to another, and for one observer been determined that many healthy adults can have these from one patient and/or one occasion to another. A study types of laryngeal alterations without association with any in which otolaryngologists evaluated laryngoscopy images LPR symptoms (42). of 120 patients showed low diagnostic reproducibility (43).

196 Rev Col Gastroenterol / 26 (3) 2011 Controversies in Gastroenterology Currently, performance of a therapeutic test is recommended when the physician has clinical suspicion that a patient has LPR and when there is a positive fi nding for LPR from laryngoscopy (46). Th erapeutic tests are not recommended for patients with gastrointestinal bleeding, anemia, abdominal pain and weight loss whose causes have not been completely studied since it is possible such patients have complex pathologies such as neoplasias (37).

CLASSIFICATION OF REFLUX FINDINGS

A subjective scale has been developed to quantify the seve- Figure 3. A Telelaryngoscopy image of a patient with LPR symptoms rity of infl ammatory changes in the larynx by identifying showing a granulomatous lesion in the posterior quarter of the free edge of the right vocal fold over the vocal process of the arytenoids. B endoscopic fi ndings related to LPR. Th is scale was created Telelaryngoscopy image of the same patient 3 months aft er beginning because LPR diagnoses based on patients’ symptoms and PPI treatment and anti refl ux control measures. Image shows that the on 24 hours pH measurements are very vague (47). granulomatous lesion in the posterior larynx has completely disappeared. Th ese subjective fi ndings for patients with LPR are clas- sifi ed using the “Refl ux Finding Score” (RFS) developed We refer patients who present additional digestive by Belafsky et al.(Table 2). Th e RFS gives a score related symptoms to gastroenterology for an upper digestive tract to laryngoscopic fi ndings. eTh maximum score is 26; a endoscopy. Nevertheless, some authors recommend per- score of 7 or greater is considered to indicate that LPR is forming an upper digestive tract endoscopy for all patients highly likely. Th is scale has been standardized so that oto- with manifestations of extra-digestive refl ux to rule out laryngologists can perform bett er diagnoses, document important anatomical defects such as hiatal incompe- the severity of symptoms and evaluate the eff ectiveness of tence and hiatal hernia that may be related to the disease. treatment (48). Upper digestive tract endoscopies can also identify other lesions including esophagitis, esophageal stenosis, Barrett ’s Table 2. “Refl ux Finding Score” (RFS). esophagus, gastric mucosal injuries and tumors (37). LPR symptoms have also been shown to be more prevalent than Findings Score typical GERD symptoms among patients with esopha- Subglottic Edema 0= absent, 2= present geal adenocarcinomas. Th ese factors support the use of Ventricular 0= none, 2= partial, 3= complete upper digestive tract endoscopy for the evaluation of these Erythema/Hyperemia 0= none, 2= arytenoids, 3= diffuse patients (44). Vocal Fold Edema 0= none, 2= mild, 3= severe, 4= polypoid In addition to upper digestive tract endoscopies a batt ery Diffuse Laryngeal Edema 0= none, 2= mild, 3= severe, 4= obstructive of other diagnostic examinations can be used for selected Posterior Commissure 0= none, 2= mild, 3= severe, 4= obstructive cases in order to determine esophageal function, response Hypertrophy to treatment and need for additional treatment. Among Granuloma/Granulation 0= absent, 2= present these is measurement of esophageal pH, esophageal gam- of Tissue magraphy, contrast x-rays of the upper digestive tract, Thick Endolaryngeal 0= absent, 2= present manometry and esophageal impedanciometry. Mucus Although the 24-hour esophageal pH test with an intragastric sensor is increasingly being used as a diagnostic tool Adapted from Belafsky PC, Postma GN, Koufman JA. Th e validity for determining GERD and LPR, it cannot be considered and reliability of the refl ux fi nding score (RFS). Laryngoscope. the “gold standard” for diagnosing an extra-digestive syn- 2001;111:1313–1317. drome because it does not reveal abnormal proximal events in a high percentage of patients with extra-digestive symp- Of the fi ndings mentioned in Table 2, erythema, aryte- toms and typical signs. Nevertheless, it is useful for evalua- noid hyperemia and vocal fold edema respond to medical ting these patients’ responses to treatment (45). treatment for refl ux (49). Other studies confi rm that vocal Due to the low specifi city of laryngoscopy and the low fold edema and erythema and the inter-arytenoid space are sensitivity of the 24-hour esophageal pH test for determi- sensitive markers for LPR (50). nation of LPR, the therapeutic test has appeared as a diag- A study of the validity of the RFS compared a group of 40 nostic method which is now accepted in clinical practice. patients who had cases of LPR confi rmed by pH measure-

Reflux laryngitis: an Otolaryngologist’s perspective 197 ments before treatment, and who were then tested at two, be followed for 2 to 3 months without changes in the same four and six months following treatment, with a control dosages until the patient is evaluated again. It has been deter- group of 40 patients with healthy larynxes. Th e study found mined that patients with laryngopharyngeal refl ux require a that the average RFS for healthy patients was 5.2 whereas more aggressive and prolonged treatment than do patients the average RFS for patients with LPR was 11.5. On the with gastroesophageal refl ux (1). With medical management basis of this study the authors consider that this index is lasting 2 or 3 months, most patients’ symptoms improve sig- reproducible, reliable and appropriate for documenting the nifi cantly; however laryngeal changes require at least 6 mon- eff ectiveness of treatment of LPR patients. Th ey conclude ths before they are resolved (39). that it is a useful tool for describing changes in laryngeal If the patient responds adequately to treatment during the tissues caused by this disease (50). test, treatment with progressively decreasing does should be maintained for 6 additional months. If the patient’s TREATMENT symptoms persist, two clinical situations are possible. Th e patient may simply haves an inadequate response to the Current recommendations try to limit indiscriminate treatment, but the possibility also exists that the cause of empirical use of anti refl ux medications for treatment of the symptoms is not refl ux (37). In the case, PPI dosage can patients with dysphonia, especially when patients have no be doubled, the PPI can be changed, or Ranitidine or asso- GERD symptoms or laryngeal disorders caused by refl ux. ciate alginates can be added to the treatment. In the second Th is is because of the known adverse eff ects of these drugs case, the study of the patient must be completed with 24 and lack of evidence that they benefi t patients with dyspho- hour pH measurement with an intragastric sensor without nia. Medical management must be directed at controlling suspending the medication to evaluate whether PPIs are infl ammatory changes of the larynx when it is documen- eff ectively suppressing acid secretion, and the patient must ted through laryngoscopic fi ndings of erythema, edema, be examined by a gastroenterologist. redundant tissue, irregularities in the interarytenoid, aryte- Alginates are currently used as an option for GERD noid, or posterior laryngeal mucosa or fi ndings of irregula- treatment and are beginning to be used for laryngopharyn- rities in the vocal folds (51). geal refl ux (LPR). eseTh alginates create a physical barrier In patients with clinical symptoms of refl ux disease with to gastric content and protect the esophageal mucosa from extra digestive manifestations, the fi rst step in treatment acid refl ux. McGlashan et al. studied 49 LPR patients who consists of diet modifi cations and anti-refl ux measures. were divided into a group which was provided with a sus- Diet modifi cations include weight loss when necessary, and pension of alginate and a group which was given placebos. avoidance of exaggerated consumption of alcoholic beve- A statistically signifi cant decrease of symptoms was found rages, coff ee, chocolate, menthol, citrus fruit, citrus juices, among the patients who received alginates (12). condiments and spicy food. Anti-refl ux measures include Today there are also other tools available for evaluation raising the head of the bed, left lateral decubitus position at of the presence of non acid refl ux as a cause of the symp- bedtime, avoidance of naps aft er eating, avoidance of sleep toms, esophageal motility and gastric emptying. Th ese until at least three hours aft er the last meal of the day, avoi- include esophageal manometry, esophageal impedance, dance of abdominal exercises aft er eating, and avoidance of adding prokinetics when emptying disorders are suspected the use corsets, belts and tight clothing. Research done by and the possibility of anti refl ux surgery. Stewart et al. showed that changes in lifestyle for 2 months, Not all patients whose medical management has failed with or without medical management with PPIs, conside- are candidates for surgical management. Th e best candida- rably improves chronic laryngeal symptoms (52). tes are those who react properly to anti-secretory therapy. As previously mentioned, many recent guidelines for Candidates for surgery should have anatomical defects management of manifestations of extra digestive refl ux, inclu- such as large hiatal hernias aff ecting the motility of the nor- ding the most recent offi cial guidelines of the Asociación mal upper gastrointestinal tract which need to be corrected. Colombiana de Otorrinolaringología (ACORL - Colombian Candidates also include those patients whose refl ux per- Association of Otolaryngology), recommend performance sists in the hypopharynx despite maximum doses of PPIs, of a therapeutic test with PPI for patients with symptoms those who have abundant refl ux material, and those with suggestive of laryngopharyngeal refl ux (LPR) and who have duodenum-gastric refl ux or refl ux complications (37,54). laryngoscopy fi ndings which are positive for LPR (53, 54). Th e idea of this test is to determine the infl uence of refl ux CONCLUSIONS on the patient’s symptoms. Th e test consists of PPI dose twice a day, once at least 30 minutes before breakfast, and Refl ux laryngitis or laryngopharyngeal refl ux is one of the again at least 30 minutes before dinner. Th e treatment must extra-digestive manifestations of gastroesophageal refl ux. It

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200 Rev Col Gastroenterol / 26 (3) 2011 Controversies in Gastroenterology