Contemporary evaluation and management of Laryngopharyngeal reflux (LPR) - Research Paper Example

? Contemporary Evaluation and Management of Laryngopharyngeal Reflux: A Literature Review Your s Introduction Larypharyngeal reflux (LPR) can be described as, ‘The back flow of gastric contents (refluxate) to the laryngopharynx and upper aerodigestive tract’ (Bulmer, 2010).This disease was previously considered to be a subset of gastroesophageal reflux disease (GERD), however, it is now recognized as a specific clinical entity, albeit with considerable overlap. Since its recognition, a notable quantity of research has been devoted to elucidating the pathogenesis of LPR, and establishing criteria and/or guidelines for the most relevant investigations and most effective management options. Although consensus has not been reached globally on these issues, generalized conclusions can be made through evidence in the literature that can guide physicians dealing with LPR patients. This paper seeks to summarize what is currently known and understood regarding laryngopharyngeal reflux. It begins with a brief historical narrative on the disease and its significance from a public health perspective, followed by a discussion of the underlying pathophysiologic mechanisms. It then reviews the literature recently published on its evaluation and management options. In conclusion, it states why it is important to recognize the disease, and reiterates the most reliable evidence in the literature regarding its diagnosis and treatment. Review of Literature A review of the literature on laryngopharyngeal reflux was carried out using the databases PubMed and GoogleScholar, which yielded more than a hundred relevant articles for the keywords ‘laryngopharyngeal reflux’. A larger number of studies exist that make reference to, or include results applying to it. However, fifteen publications were selected to be included in this review. Although this review is exhaustive and has attempted to include all that is known regarding the evaluation as well as management of LPR, a significant number of studies were not included in the referencing as they merely reiterated or repeated conclusions of another more reliable study. A number of studies presented ambiguous or inconclusive findings, they could not contribute to the discussion in this review and were excluded. Furthermore, a number of reviews have been published over the years, and recently in 2011 as well, that discuss the results of several studies in combination. This review incorporates the discussion from those reviews, therefore, the individual studies that sourced those reviews have not been delved into. The ultimate aim was to provide an overview that is as contemporary as possible. Discussion Overview and History Reflux of gastric contents upwards into the esophagus and beyond, giving rise to the feeling of heartburn and taste of regurgitation, has long been recognized as an illness termed ‘gastroesophageal reflux disease’ (GERD). The concept of gastric reflux with resultant esophageal mucosal injury was recognized as early as 1935. Effects of reflux on the throat, such as cough, were also recognized, indeed, cough was considered a significant symptom of GERD. However, it was not until 1968 that Cherry and Margulies described the role of gastroesophageal reflux in laryngeal disease (Schreiber, 2009). Physicians eventually came to recognize that the significant effects of reflux on the larynx seemed to produce a different set of symptoms than those experienced in simple GERD. In 1987, Ossakow et al. conducted a study showing that patients with persistent cervical complaints frequently had acid reflux (68%) and poor acid clearance (79%) confirmed by esophageal manometrics and acid reflux testing, however, they did not commonly report complaints of pyrosis or regurgitation (Ossakow, 1987). Symptoms of LPR do not typically include the heartburn that is classic in GERD, and include hoarseness, sore throat, frequent throat clearing or globus sensation (Zerbib, 2010). The American Academy of Otolaryngology formally adopted the term ‘laryngopharyngeal reflux’ in 2002 to describe the illness that included these symptoms (Bulmer, 2010). They defined LPR as the association of these laryngeal symptoms with laryngeal inflammation seen with laryngoscopy. Epidemiology and Risk Factors Between 21-60% of the population in the United States experiences reflux symptoms (Locke, 1997). The risk factors identified for GERD and LPR are, as yet, similar, and include consumption of chocolate, alcohol, fried food, fatty products, tomato-based products; smoking, and increased intra-abdominal pressure due to obesity (Schreiber, 2009). Pathogenesis The mechanisms of laryngeal injury in laryngopharyngeal reflux are not completely explained, although several studies have outlined involved factors. Two main mechanisms are hypothesized to underlie laryngeal disorders due to reflux: first, that acidic reflux into the esophagus sets off a vagal stimulus, that promotes symptoms such as coughing and reflex bronchospasm. Second, that the direct contact of acid and pepsin in the gastric refluxate mediates mucosal damage on the larynx (Schreiber, 2009). A previous review (Sataloff, 2010) based on the findings of earlier studies, showed that esophageal biopsy findings can be normal in up to 72% of patients with LPR. This is consistent with tha fact that a significant number of LPR patients do not have symptoms of GERD such as heartburn. Sataloff et al. explain that this is possibly because the brief reflux episodes that bring gastric refluxate in contact with the delicate laryngeal epithelium and cause inflammation in LPR are unable to inflict injury on the more resistant squamous epithelium of the esophagus, which is better adapted to tolerating acid exposure. Ford (2005) after reviewing literature on reflux-related laryngitis, proposed the following mechanism for LPR: Under physiologic circumstances, the larynx and pharynx are protected from gastric reflux by the tone of the closed lower and upper esophageal sphincters, the motor function of the esophagus to clear acid, and resistance of the esophagus lining to acidic damage. Failure of these barriers allows gastric refluxate to reach the delicate ciliary epithelium of the posterior larynx, damaging it so that it cannot perform its regular function of clearing mucus from the tracheobronchial tree. This leads to accumulation of mucus in the larynx, stimulating cough and throat-clearing. The local inflammation caused by acid damage promotes formation of vocal fold edema, contact ulcers and granulomas: these are likely to cause the symptoms of hoarseness, globus and sore throat. Bulmer et al. (2010) investigated the effects of gastric refluxate on the laryngeal mucosa, using tissue sections from porcine larynges exposed in vitro to solutions comparable to gastric refluxate contents. They reported that hydrochloric acid and pepsin are the main components of gastric refluxate that mediate mucosal damage in the larynx, however, the acid alone is not sufficient to cause injury, as it is diluted by the secretions of the esophagus. Pepsin is a potent enzyme that digests proteins in food in the stomach in the presence of acid, that retains some of its digestive activity at a pH of up to 5-6.Their study, which evaluated the degree of damage to different areas of the larynx after exposure to acid, pepsin, and both acid and pepsin together, showed that acidic solutions on contact with the larnx produce significantly more damage than solutions of neutral pH, however, pepsin-containing acid solution produced more tissue damage than acid solutions of similar pH without pepsin. Also, acid as strong as a pH of 4.0 could not produce laryngeal injury unless accompanied by pepsin. Thus, their results established the significant role of destructive enzymes in producing injury. Furthermore, they found that the columnar epithelium beneath the vocal folds was the area of the larynx most susceptible to reflux-mediated damage. The vocal folds were also susceptible, despite being lined by the tougher squamous epithelium. This damage to vocal fold mucosa would explain the symptom of hoarseness, that is experienced by a majority of patients with LPR. The authors also suggested that bile salts and pancreatic enzymes may play a role in reflux-mediated damage, this is yet to be thoroughly investigated. A review (Galli, 2006) on this topic concluded that the biliary component of the refluxate may potentially be involved in reflux-related inflammatory, precancerous and neoplastic laryngeal lesions, and recommended that anti-reflux therapy as treatment should focus on not only the gastric, but also the duodenal component. In a similar study by an international collaborative research group, Johnston et al. (2003) demonstrated that pepsin is detected in biopsies from the larynx of LPR patients, but not in normal subjects. They also found the depletion of carbonic anhydrase III enzyme (CAIII), which normally neutralizes acids, in association with the presence of pepsin in laryngeal folds and ventricles. CAIII depletion by gastric acid thus seems to be involved in reflux-related inflammatory damage in the larynx, as it allows the acid to turn on the cells and cause damage and inflammation.The investigators also found reduced E-cadherin, a molecule involved in cellular adhesion, in LPR samples. They concluded that laryngeal epithelium lacks the prtotective defenses present in esophageal epithelium, making it more susceptible to reflux-related injury. Helicobacter pylori infection-associated gastritis has been associated with greater severity of GERD, following this thread led Youssef et al. to find a high prevalence rate of 57% for H. pylori infection in LPR patients. They also found that these patients experienced better improvement in symptoms when antibiotic therapy with amoxicillin and clarithromycin, targeted at treating the H.pylori infection, was added to the acid-suppressive regimen for LPR treatment. Thus, H.pylori gastritis seems to be associated with LPR and GERD. Evaluation: Clinical Significance and Symptoms As mentioned earlier, the significant symptoms of LPR include throat clearing (98%), persistent cough (98%), globus pharyngeus (feeling of lump in throat) (95%), and hoarseness (95%) (Ford, 2005). LPR appears to be present in about 50% of all patients that present with voice disorders (Sataloff, 2010). It is essential for the physician to be able to recognize LPR reflux from simple GERD and treat it effectively, as reflux may have consequences beyond a few simple symptoms. Chung et al. (2009) investigated the prevalence of LPR in patients with known benign vocal cord lesions, and found it to be significantly more common in patients with Reinke’s edema and vocal polyps. It is therefore postulated to contribute to the development of these lesions. LPR also causes posterior laryngitis, laryngeal contact ulcers, laryngeal stenosis or granuloma formation, laryngeal edema with erythema, chronic hoarseness, pharyngitis, poorly controlled asthma, nocturnal choking, and stridor in infants (Schreiber, 2009). It has even been suggested that duodenogastroesophageal reflux may play a role in the development of esophageal and laryngeal cancer (Schreiber, 2009). A recent study by Kyung et al. (2011) verified these concerns, where they found a significantly higher prevalence of LPR in laryngeal cancer patients than normal subjects – although the results may have been confounded by differences in smoking and alcohol consumption between the groups. Indeed, one study found LPR to be more common than GERD in patients with esophageal carcinoma, and may be the only signs of the disease (Reavis, 2004). In children, extra-esophageal reflux is associated with upper respiratory tract illnesses, including chronic otitis media and otitis media with effusion, these children benefit from antireflux treatment, as it reduces ear symptoms (Gibson, 1994). In such cases, it is hypothesized that the reflux contents make their way to the nasopharynx and then through the eustachian tube to the ear, stimulating inflammation. Laryngopharyngeal reflux is different from gastroesophageal reflux disease in several important ways. Patients with GERD mostly suffer from a supine nocturnal reflux along with disorders of esophageal motility, whereas LPR patients have upright daytime reflux, and normal esophageal motility. Moreover, patients with laryngeal reflux seem to have good esophageal acid clearance compared to GERD patients (Schreiber, 2009). Evaluation: What tests to order and when? There has been controversy as to whether LPR symptoms warrant investigation with esophageal investigations such as endoscopy and pH testing, and which tests are most adequate initially. Although there is insufficient data on the incidence of complications of LPR to categorically accept or reject the notion of screening, some researchers are of the opinion that the esophagus should be screened routinely in patients diagnosed with LPR (Remacle M, 2006). This is because LPR may not be adequately diagnosed on clinical features alone. Symptoms of LPR are non-specific and could be produced by a number of etiologies: viral or bacterial infection of the larynx, allergy, vocal trauma, and post-nasal drip (Ford, 2005). An important example here is laryngeal carcinoma: it is advised that any patient with hoarseness lasting 2 or 3 weeks should undergo visualization of the larynx to rule out this condition (Ford, 2005). A review on LPR has also concluded that a laryngeal examination is mandatory for a patient presenting with vocal difficulties (Sataloff, 2010). LPR may be associated with higher severity of acid-related damage in the esophagus, raising the risk for Barrett’s or adenocarcinoma in the esophagus, which needs to be promptly diagnosed and treated. Thus, Altman (2011) concluded that based on current data available, it would be advisable to perform esophageal testing on patients with at least ‘moderate’ or ‘high’ risk symptoms of LPR. This categorization of symptoms is described later in the rivew. Diagnosis of LPR may be established on a positive response to empiric PPI treatment alone. This approach has been found to have a sensitivity greater than 90%, but a specificity of only 14% (Masaany, 2011). It is, therefore, possible for many LPR patients to not respond to acid-suppressant therapy, requiring other/additional diagnostic and treatment strategies. The main diagnostic tools that are used by otolaryngolosists to diagnose LPR include laryngoscopy and reflux monitoring (Abou-Ismail, 2011). On laryngoscopy, the diagnosis of LPR is based on visualization of erythema and edema of the larynx, which can be seen in more than 80% of patients with LPR (Sataloff, 2010). However, the specificity of these signs for LPR is low, as they may be associated with other causes or be found in healthy individuals. Ambulatory 24-hour double-probe pH monitoring of the distal esophagus,which is indicated for evidence of reflux-related esophaeal inflammation, also has low sensitivity in diagnosing GERD-related laryngeal findings. Oesophageal pH is recorded in supine, upright, and postprandial positions. Positive test criterion for diagnosis of GERD has been taken as ?5% for the percentage of total time over 24 hours as pH less than 4. On the other hand, LPR diagnosis is accepted for the following findings: at least three episodes of pH below 4 in the proximal probe (in upper esophagus) with a simultaneous drop in pH < 4 in the distal probe, or ?1% for the percentage of total time pH < 4 in the proximal probe (Ozmen, 2011). In simpler words, pathologic LPR is defined as more than 3 episodes of LPR within a 24-hour period (Tae, 2011). Although pH monitoring is considered as the gold standard for diagnosing LPR according to some authorities, its sensitivity is reported to be lower than 50% (Ozmen, 2011). Oppnonents of the test also argue that it is a costly and a time-consuming test, and cannot detect intermittent reflux episodes or non-acidic reflux episodes. A definitive conclusion on this issue was provided by a meta-analysis on the utility of the pH probe in diagnosing LPR, which concluded that the upper probe gives accurate, reliable and consistent information in normal subjects and patients with LPR. It also found that the numbers of reflux events and acid exposure times helped distinguish normal subjects from patients with LPR (Merati, 2005). Other investigations suggested for patients with LPR to detect esophageal pathology include transnasal endoscopy (TNE), esophagogastroduodenoscopy (EGD), barium esophagogram (BAS) and scintigraphy. There are advantages and disadvantages associated with each, and the best choice may be individualized to the patient. The accuracies of these tests are reported for diagnosis for GERD, not LPR (Altman, 2011). The endoscopy techniques, EGD and TNE, are more expensive and require paitent sedation, however, they allow biopsies to be taken to evaluate Barrett’s and carcinoma. Barium esophagogram, although not as sensitive, is less expensive, does not require sedation, and is better for evaluating a dysmotility disorder. New diagnostic techiniques for evaluation of LPR remin under investigation. Yu et al. (2011) recently published a study on the potential of measuring pepsin levels in sputum of LPR patients as a diagnostic tool, and mode of measuring response to acid suppressant therapy. They concluded that it may prove to be an objective, effective tool (Yu, 2011). Further studies will be needed to validate these claims. A number of clinical scoring systems such as the Reflux Symptom Index have been created and used to diagnose LPR on clinical and laryngoscopy findings (Sataloff, 2010), however, their reliability and reproducibility remains to be confirmed by further studies. Management of Laryngopharyngeal Reflux There are no established guidelines on the evaluation and management of LPR, this is attributable to the tendency of physicians to combine LPR ang GERD into a clinical entity described as ‘reflux disease’, while the pathophysiologic and clinical disparities between the two illnesses requires that a slightly different approach be employed for each of them. Still, Altman et al. (2011) have devised a primary algorithm for the evaluation and management of reflux disease and its complications, outlining a scheme that could consistently be followed by primary physicians, gastroenterologists and otolaryngologists alike. It proposes stratifying the patient presenting with reflux symptoms as low risk, moderate risk or high risk based on the severity of clinical presentation, and recommends what further testing and treatment should be done for each group. The algorithm emphasizes reserving diagnostic tests for moderate or high risk patients, and restricting the dose of acid auppressive therapy to the minimum that is effective. The purpose of further testing is to identify whether the symptoms are due to inflammation alone, or whether a more serious pathology such as barrett’s esophagus or laryngeal carcinoma is present. Low-risk patients– those with incidental symptoms and symptomatic nuisance, should be given empiric therapy with lifestyle and diet modification and intermittent acid-suppressive medication – proton pump inhibitors or H2 blockers – for a time until the symptoms resolve. If symptoms do not resolve or the patient continues to worsen, esophageal screening is then recommended. First-line screening methods that were recommended include esophagogastroduodenoscopy (EGD), transnasal endoscopy (TNE), or barium esophagogram (BAE). Any positive findings on these tests should be treated accordingly, while for negative results on these tests, further testing with manometry and esophageal pH testing to confirm the diagnosis is then recommended. Moderate risk patients are described as those with age above 50 years, dysphagia, odynophagia, anemia, weight loss, respiratory disturbance, and nocturnal awakening. These patients are at risk of, or are likely to have bilious regurgitation, a motility disorder, significant hiatal hernia, Barrett’s metaplasia, or complications of LPR: including but not limited to cricopharyngeal spasm, laryngospasm,vocal process granuloma, disabling cough, and aspiration pneumonitis.Thus, these patients should be sugjected to an initial screening test which would identify any of the above abnormalities, so that appropriate therapy can be given. High risk patients classify as those with sever odynodysphagia, hematemesis, hemoptysis, abdominal pain, significant weight loss, and respiratory distress or laryngospasm. These patients require urgent direct screening with EGD, as they are at risk of esophageal carcinoma or other mediastinal mass causing laryngeal/esophageal compression.The treatment strategy for moderate and high risk patients with no findings on these tests may require treatment with, in addition to acid suppression therapy, also motility agents, muscle relaxants, CP myotomy, and laparoscopic fundoplication. A portion of the patients may have exaggerated symptoms without severe inflammation due to heightened sensory perception, and they would also benefit from antidepressants, gabapentin, or behavioral therapy. With regards to management, proton pump inhibitors (PPI) therapy remain the cornerstone of treatment for LPR (Abou-Ismail, 2011). The current management recommendation for this group of patients is empiric therapy with twice-daily PPIs for 1 to 4 months (Vaezi, 2006). Also, for these patients, diagnostic testing with prolonged pH monitoring may be indicated. Moreover, the usefulness of adding prokinetics to proton pump inhibitors (PPIs) in the treatment of LPR was assessed by Ezzat et al (2011). They concluded on the basis of their findings that addition of the prokinetic agent itopride to the 8-week regimen of a PPI improves the clinical outcome, shortens the need for oral medication, and reduces the rates of recurrence of symptoms of LPR. Many patients who are diagnosed initially with GERD with laryngeal symptoms may fail to show symptomatic or laryngoscopic response to acid suppression, and may not have abnormal esophageal acid levels on pH monitoring. Vaezi et al. (2006) were of the view that such patients may have irritation of the larynx due to causes other than GERD, leading to the failure of PPIs in resolving symptoms. This is an important evaluating factor to keep in mind. H.pylori infection has been found to be associated with documented reflux, and patients with LPR may have concurrent H.pylori infection (Youssef, 2010). Antibiotic therapy aimed at H.pylori eradication may achieve better symptom reduction in these patients. H.pylori stool antigen testing could be included in the investigations for patients with long-standing reflux, or reflux not responding well to acid suppressive therapy alone. Surgical fundoplication is a choice of therapy reserved for patients with moderate to severe LPR. It is most effective in those who are responsive to acid-suppressive therapy (Abou-Ismail, 2011). Trad et al. (2011) evaluated the safety and effectiveness of transoral incisionless fundoplication (TIF) in treating patients of GERD and LPR. Their results were encouraging, they found that after the procedure, 82% of patients were off daily PPIs at the 14-month follow-up. Symptoms of LPR such as hoarseness, coughing, and throat clearing were eliminated in 63% of the patients. Regurgitation and heartburn also resolved in a majority of patients. Thus, surgical fundoplication seems to be an effective method for treating LPR that has not responded to initial acid suppressant therapy. Its impact on preventing complications of LPR and GERD, such as esophageal carcinoma, could be further evaluated. Conclusion This literature view aimed to summarize the medical community’s current understanding and consensus on a relatively new clinical entity, laryngopharyngeal reflux. Based on the publications that were discussed, the following can be concluded. Laryngopharyneal reflux is the outcome of mucosal damage inflicted on the larynx by acid and pepsin in the gastric refluxate. Pepsin plays a major role as acid alone cannot produce significant laryngeal inflammation. Biliary and pancreatic secretions seem to be present in the refluxate and also mediate inflammatory damage. Patients with laryngopharyngeal reflux report complaints of cough, hoarseness, globus senstation and throat irritation, while they often do not have clinical features of gastroesophageal reflux, such as heartburn or regurgitation. LPR also predominantly involves daytime upright reflux, while reflux in GERD is mostly post-prandial and associated with lying supine. The diagnosis of LPR cannot be based on clinical features alone, as these are non-specific. Diagnosis may be based on response to acid-suppressive therapy, laryngoscopic findings of inflammation, or acidic pH of upper esophagus on 24-hour ambulatory esophageal pH monitoring. Other investigations to consider include barium studies and scintigraphy. Patients with LPR may occasionally have another underlying pathology, including vocal polyp, laryngeal granuloma, laryngeal stenosis, Barrett’s metaplasia, and possibly laryngeal or esophageal cancer. These are associated with more severe and long-term acid exposure. Therefore, patients with significant features of LPR should undergo some form of esophageal screening, such as barium esophagogram or endoscopy. Also, LPR treatment is all the more important, as it may help prevent these ominous complications. The current recommendations for LPR treatment includes initial acid-suppressant therapy with PPIs or H2 blockers, which can be started empirically in mildly symptomatic patients. Alternative etiologies, such as allergy or infection, should be considered in patients who do not respond to acid suppression. Patients, especially those with more severe symptoms such as dysphagia, may also benefit from additional therapy with prokinetic agents. H.pylori testing and its treatment with antibiotics may also improve symptoms. Surgical fundoplication is a safe and effective intervention for more severely symptomatic patients, however, it provides greater benefit to patients who showed a good response to acid suppressive therapy. 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