Treatment of Clinically Diagnosed Laryngopharyngeal Reflux Disease

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ORIGINAL ARTICLE

Treatment of Clinically DiagnosedLaryngopharyngeal Reflux DiseaseTarek Fouad Youssef, MD; Mohamed Rifaat Ahmed, MD

Objectives: To determine the incidence of Helicobac-ter pylori (HP) stool antigen (HPSA) in patients with la-ryngopharyngeal reflux disease (LPRD), and to make acomparison of 2 treatment regimens that have been usedbased on the presence or absence of HPSA positivity inpatients with LPRD.

Design: Randomized controlled study.

Setting: Suez Canal University Hospital, Ismalia, Egypt.

Patients: A total of 212 patients with symptoms of LPRD.

Intervention: Patients were evaluated by laryngoscopy,ambulatory pH monitoring for 24 hours, and HPSA test-ing. Esomeprazole magnesium as a monotherapy was evalu-ated vs triple therapy in patients with HP infection.

Main Outcome Measures: To determine the inci-dence of HPSA in patients with LPRD, and to make a com-parison of 2 treatment regimens that have been used basedon the presence or absence of HPSA positivity in pa-tients with LPRD.

Results: Persistent dry cough and a feeling of a lump inthe throat (globus sensation) were the most frequentsymptoms of LPRD, while posterior laryngeal inflamma-tion was the main laryngoscopic finding. Results fromthe HPSA test were positive in 57% of the studied group.Patients with negative HPSA were treated with esomepra-zole as single modality with a reported improvement scoreof 96.6%. Patients with positive HPSA test results weredivided into 2 groups: 1 received only esomeprazole, withreported improvement in 40%, whereas the second groupwas treated with esomeprazole, plus amoxicillin so-dium and clarithromycin (triple therapy) and reporteda 90% incidence of symptom improvement.

Conclusion: The incidence of HP infection in patients withLPRD in our study was 57%. Triple therapy showed a highercure rate in patients with HPSA-positive test results.

Arch Otolaryngol Head Neck Surg. 2010;136(11):1089-1092.Published online September 20, 2010.doi:10.1001/archoto.2010.165

G ASTROESOPHAGEAL RE-flux disease (GERD) isdefined as a backwardflow of gastric contentsinto the esophagus.1 Bea-

ver et al2 suggested that laryngopharyn-geal reflux disease (LPRD) means a back-ward flow of the stomach contents up tothe throat. The clinical symptoms usu-ally occur secondary to a refluxate of hy-drochloric acid and pepsin.3 The gastricrefluxate in the larynx might be the caus-ative factor in posterior laryngeal inflam-mation, laryngeal contact ulcers, and la-ryngeal granuloma formation.3,4 It isassociated with many otolaryngology dis-orders, such as reflux laryngitis, cervicaldysphagia, globus pharyngeus, chroniccough, laryngeal or tracheal stenosis, andlaryngeal carcinoma.4 The incidence of la-ryngopharyngeal symptoms is greater thanexpected.5

There is a complex multifactor set ofpathophysiologiccharacteristicsofLPRDbe-sides simpleacidreflux.6 Helicobacterpylori(HP)isagram-negative,microaerophilicbac-terium that can cause infection of the stom-ach and is also strongly linked to the devel-opment of duodenal and gastric ulcers.7,8 ArelationshipbetweentheratesanddegreeofrefluxesophagitiswithHPinfectionhasbeenreported,but toourknowledge,norelation-ship with reflux laryngitis has been re-ported.9,10 TheHPstoolantigen(HPSA)testis a rapid, noninvasive diagnostic methodbasedonasandwichenzyme immunoassaywithantigendetection,whichhasahighsen-sitivity and specificity.11,12

No standard guidelines are available fortreatment of LPRD; proton pump inhibi-tors, twice daily for 8 weeks, have been rec-ommended13 if HP is present. However,clinical guidelines may consider revisionto add a triple therapy regimen.

Author Affiliations:Department ofOtolaryngology–Head and NeckSurgery, Faculty of Medicine,Suez Canal University,Ismalia, Egypt.

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We determined the incidence of HPSA-positive find-ings among patients diagnosed as having LPRD and com-pared the efficacy of 2 treatment regimens.

METHODS

We performed a randomized controlled study at Suez CanalUniversity Hospital, Ismalia, Egypt. A total of 212 patients withLPRD symptoms (hoarseness, chronic unexplained cough, fre-quent throat clearing, a feeling of a lump in the throat [globussensation], and a bad or bitter taste in the mouth3) were in-cluded in this study, but we excluded patients with a historyof smoking, alcohol intake, chronic rhinosinusitis, or treat-ment for LPRD.

All patients underwent laryngoscopic examination to con-firm reflux signs, then 24 hours of pH monitoring was or-dered (the pH test was considered to be positive for LPRD whenthe pH was lower than 4; HPSA testing was ordered when afresh stool sample was obtained).11,12

Patients with negative HPSA test results received once-daily esomeprazole magnesium, 40 mg, for 4 weeks.14 Patientswith positive HPSA test results were divided into 2 equal ran-domized groups: one was a control group that received onlyesomeprazole magnesium, 40 mg, for 4 weeks,14 and the otherwas a study group that received triple therapy comprisingesomeprazole magnesium, 40 mg, plus amoxicillin sodium, 1g, and clarithromycin, 500 mg, for the same period.14

A senior otolaryngologist (T.F.Y.) who was blind to the treat-ment protocol performed follow-up evaluation for all patientsafter the end of medical treatment.

RESULTS

The mean age of the 212 patients in the study was 32.4years. Cough, the main LPRD symptom, was found in105 patients (49%), followed by globus sensation in 98patients (46%), frequent throat clearing in 78 patients(36%), a bad or bitter taste in the mouth in 69 patients(32%), and hoarseness in 54 (25%).

Red, irritated arytenoids was the main laryngoscopicfinding in 116 patients (54%), followed by swelling ofthe vocal cords in 59 patients (27%), small laryngeal ul-cers in 24 patients (11%), and laryngeal granulomas in4 patients (2%).

Among the patients in the study, the HPSA test resultswere positive in 57% of cases, and we found them to bestatistically nonsignificant in relation to patient symp-toms (Table 1) (P� .05 was considered statistically sig-nificant). Also, they were found to be nonsignificant in re-lation to the laryngoscopic findings (Table 2).

Markedimprovement insymptomsoccurredin87of the90patientswithnegativeHPSAtestresultswhoreceivedonce-daily esomeprazole magnesium, 40 mg, for 4 weeks.14

The 122 patients with positive HPSA test results wererandomized into 2 equal groups (61 patients each). Thecontrol group (61 patients) received only esomeprazolemagnesium, 40 mg, for 4 weeks; 23 patients (40%) showedmarked improvement in symptoms, partial improve-ment occurred in 9 patients (16%), while 25 patients(44%) reported no improvement. Four patients discon-tinued follow-up.

The second study group (61 patients) received tripletherapy comprising esomeprazole magnesium, 40 mg, plusamoxicillin sodium, 1 g, and clarithromycin, 500 mg,14

for the same period. Two patients discontinued follow-up. Fifty-three patients (90%) showed marked improve-ment in symptoms, partial improvement occurred in 3patients (5%), and 3 patients (5%) showed no improve-ment (Figure).

COMMENT

In the practice of otolaryngology, it is now common to en-counter patients with LPRD symptoms. Most of these pa-

Table 1. Relationship Between Laryngopharyngeal RefluxDisease (LPRD) Symptoms With HPSA Test Resultsa

LPRD Symptom

Patients With HPSATest Result, No.

Positive(n=122)

Negative(n=90)

Chronic cough 59 46Feeling of lump in throat 52 46Frequent throat clearing 40 38Bad/bitter taste 37 32Hoarseness 24 30

Abbreviation: HPSA, Helicobacter pylori stool antigen.aAll comparisons were nonsignificant (P� .05 was considered statistically

significant).

Table 2. Relationship Between Laryngoscopic Findingsand HPSA Test Resultsa

Laryngoscopic Findings

Patients With HPSATest Result, No.

Positive(n=122)

Negative(n=90)

Red, irritated arytenoids 61 55Swelling of the vocal cords 32 27Small laryngeal ulcers 11 13Granulomas in the larynx 2 2

Abbreviation: HPSA, Helicobacter pylori stool antigen.aAll comparisons were nonsignificant (P� .05 was considered statistically

significant).

100

60

80

40

20

0Study Group

(Triple Therapy)Control Group

(Treated With Esomeprazole Magnesium)

Impr

ovem

ent R

ate,

%

Figure. The clinical improvement in both controls and study patients withlaryngopharyngeal reflux disease is seen. Triple therapy comprisedesomeprazole plus amoxicillin sodium and clarithromycin. In both groups,treatment was daily for 4 weeks.




tients have been seen in thoracic and gastroenterology de-partments with atypical GERD symptoms. Laryngopha-ryngeal reflux disease is a diagnostic dilemma given thelack of solid guidelines for diagnosis and management.

In a recent report, Barry and Vaezi state,15 “more ques-tions than answers” were given, which best describes thecurrent state of knowledge of LPRD. Our current studycontributed several more questions.

In 1 limb of the study, a trial was made to associateHP infection with the degree or severity of symptoms andlaryngoscopic findings. It was shown clearly based on sta-tistical analysis that HP has no relation with any of thesymptoms or signs of HPSA-positive or HP-negativeindividuals.

The second limb of the study compared the efficacyof proton pump inhibitor monotherapy vs triple therapy,and we have shown in our results that triple therapy gavebetter results in patients with positive HPSA test results.This study presents as much raw data as possible in com-pliance with the most recent guidelines to enable futureevidence-based meta-analysis.

Gastroesophageal reflux disease is a common acid-related disorder presenting with a broad spectrum ofsymptoms with or without complications.3 The inci-dence of laryngopharyngeal symptoms is greater than ex-pected.5 There are more complex multifactorial patho-physiologic characteristics of LPRD than simply acidreflux.6 Laryngopharyngeal reflux disease is consideredto be a variant of GERD in which the incidence of throatand laryngeal symptoms is more evident and encoun-tered in practice more often than expected.16

A large number of studies have raised the issue of therole of HP infection and its role in the pathophysiologicmechanism of GERD, but the interest in its role in LPRDhas not been adequately studied.17 An estimated preva-lence rate of HP infection of 30% among the general popu-lation has been given and shows that it is quite com-mon.18 Various theories and mechanisms have beenproposed to clarify its role in GERD.

In our study, 212 patients with symptoms of LPRD andpositive results from 24 hours of pH monitoring were evalu-ated clinically. The most common symptoms were dry, per-sistent cough (49%) followed by a globus sensation (46%);other studies have also reported a globus sensation or throat-clearing, voice change, persistent sore throat, dysphagia,and cough as the predominant symptoms.19-21

The common reported findings of LPRD are in the do-main of posterior laryngitis; we reported red, irritated ary-tenoids in 54% and swollen vocal folds (27%); other re-ports20,21 found endoscopic abnormalities in up to 98%of patients with LPRD, including nonspecific hyper-emia, usually of the posterior larynx.

In our study, the 57% incidence rate of positive HPSAtest scores is higher than that reported by Haruma et al,21

who mentioned that in Japan there is a relationship be-tween HP infection and LPRD with a reported incidenceof 31% to 41%. Helicobacter pylori stool antigen testingis a relatively new, noninvasive diagnostic technique withhigh sensitivity and specificity11,22

Several authors suggested a correlation of HP infec-tion and the degree of GERD,9,10,19,23,24 while others25 didnot find any association between HP positivity and symp-

toms; the latter is in agreement with our data, which failedto demonstrate such a connection, and this variable re-port adds more to the dilemma of diagnosing LPRD.

As mentioned in the introductory paragraphs, we didnot aim to point to a specific treatment regimen, a taskbetter left for meta-analysis trials, but our raw datashowed that patients with LPRD and with negativeHPSA test results benefit from esomeprazole magne-sium, 40 mg, for 4 weeks, with marked symptomimprovement in most cases. While the patients withpositive HPSA test results who received only esomepra-zole magnesium, 40 mg, for 4 weeks showed a 40% rateof improvement, the second study group of patientswith positive HPSA test results receiving triple therapyshowed a 90% rate of improvement. Reports of a moresuccessful triple therapy in GERD26 are in agreementwith our results, but still, no clear guidelines for treat-ment of LPRD are available.

In conclusion, the incidence of the HP infection in pa-tients with LPRD in our study is 57%. Second, HP infec-tion should be considered when treatment is prescribedto patients with LPRD because the standard therapy forGERD might be insufficient. Finally, the use of tripletherapy (esomeprazole magnesium, 40 mg, plus amoxi-cillin sodium, 1 g, and clarithromycin, 500 mg) in thetreatment of LPRD with HP infection might result in ahigher cure rate.

Submitted for Publication: March 9, 2010; final revi-sion received June 20, 2010; accepted July 22, 2010.Published Online: September 20, 2010. doi:10.1001/archoto.2010.165Correspondence: Mohamed Rifaat Ahmed, MD, Depart-ment of Otolaryngology–Head and Neck Surgery, Fac-ulty of Medicine, Suez Canal University, Ismalia, Egypt([email protected]).Author Contributions: Both authors had full access toall the data in the study and take responsibility for theintegrity of the data and the accuracy of the data analy-sis. Analysis and interpretation of data: Youssef and Ahmed.Critical revision of the manuscript for important intellec-tual content: Youssef and Ahmed. Statistical analysis:Youssef and Ahmed. Obtained funding: Ahmed. Admin-istrative, technical, and material support: Ahmed.Financial Disclosure: None reported.

REFERENCES

1. Koufman JA. Gastroesophageal reflux disease. Otolaryngol Head Neck Surg. 1993;81(9)(suppl 2):2351.

2. Beaver ME, Stasney CR, Weitzel E, et al. Diagnosis of laryngopharyngeal refluxdisease with digital imaging. Otolaryngol Head Neck Surg. 2003;128(1):103-108.

3. Bough ID Jr, Sataloff RT, Castell DO, Hills JR, Gideon RM, Spiegel JR. Gastro-esophageal reflux laryngitis resistant to omeprazole therapy. J Voice. 1995;9(2):205-211.

4. Hanson DG, Kamel PL, Kahrilas PJ. Outcomes of antireflux therapy for the treat-ment of chronic laryngitis. Ann Otol Rhinol Laryngol. 1995;104(7):550-555.

5. Dinis PB, Subtil J. Helicobacter pylori and laryngopharyngeal reflux in chronicrhinosinusitis. Otolarygol Head Neck Surg. 2006;134(1):67-72.

6. Reimer C, Bytzer P. Management of laryngopharyngeal reflux with proton pumpinhibitors. Ther Clin Risk Manag. 2008;4(1):225-233.

7. Kim JG. Treatment of Helicobacter pylori infection [in Korean]. Korean JGastroenterol. 2005;46(3):172-180.




8. Yamaoka Y, ed. Helicobacter pylori: Molecular Genetics and Cellular Biology. Nor-wich, England: Caister Academic Press; 2008.

9. Oridate N, Takeda H, Yamamoto J, et al. Helicobacter pylori seropositivity pre-dicts outcomes of acid suppression therapy for laryngopharyngeal refluxsymptoms. Laryngoscope. 2006;116(4):547-553.

10. Tezer MS, Kockar MC, Kockar O, Celik A. Laryngopharyngeal reflux finding scorescorrelate with gastroesophageal reflux disease and Helicobacter pylori expression.Acta Otolaryngol. 2006;126(9):958-961.

11. Gulcan EM, Varol A, Kutlu T, et al. Helicobacter pylori stool antigen test. IndianJ Pediatr. 2005;72(8):675-678.

12. Oderda G, Rapa A, Ronchi B, et al. Detection of Helicobacter pylori in stool speci-mens by non-invasive antigen enzyme immunoassay in children: multicentre Ital-ian study. BMJ. 2000;320(7231):347-348.

13. Scott LJ, Dunn CJ, Mallarkey G, Sharpe M. Esomeprazole: a review of its use inthe management of acid-related disorders. Drugs. 2002;62(10):1503-1538.

14. Ni YH, Lin JT, Huang SF, Yang JC, Chang MH. Accurate diagnosis of Helicobac-ter pylori infection by stool antigen test and 6 other currently available tests inchildren. J Pediatr. 2000;136(6):823-827.

15. Barry DW, Vaezi MF. Laryngopharyngeal reflux: more questions than answers.Cleve Clin J Med. 2010;77(5):327-334.

16. Thomson ABR, Barkun AN, Armstrong D, et al. The prevalence of clinically sig-nificant endoscopic findings in primary care patients with uninvestigated dys-pepsia: the Canadian Adult Dyspepsia Empiric Treatment–Prompt Endoscopy(CADET-PE) study. Aliment Pharmacol Ther. 2003;17(12):1481-1491.

17. Issing WJ, Karkos PD, Perreas K, Folwaczny C, Reichel O. Dual-probe 24-hour

ambulatory pH monitoring for diagnosis of laryngopharyngeal reflux. J Laryn-gol Otol. 2004;118(11):845-848.

18. Ahmad I, Batch AJ. Acid reflux management: ENT perspective. J Laryngol Otol.2004;118(1):25-30.

19. Pinar E, Oncel IS, Calli C, Atalay M. Detection of gastroesophageal reflux by scin-tigraphy in patients with laryngopharyngeal symptoms and findings [in Turkish].Kulak Burun Bogaz Ihtis Derg. 2003;10(4):153-158.

20. Yorulmaz I, Ozlugedik S, Kucuk B. Gastroesophageal reflux disease: symptomsversus pH monitoring results. Otolaryngol Head Neck Surg. 2003;129(5):582-586.

21. Haruma K, Hamada H, Mihara M, et al. Negative association between H. pyloriinfection and reflux esophagitis in older patients: case-control study in Japan.Helicobacter. 2000;5(1):24-29.

22. Rouev P, Chakarski I, Doskov D, Dimov G, Staykova E. Laryngopharyngeal symp-toms and gastroesophageal reflux disease. J Voice. 2005;19(3):476-480.

23. Tauber S, Gross M, Issing WJ. Association of laryngopharyngeal symptoms withgastroesophageal reflux disease. Laryngoscope. 2002;112(5):879-886.

24. Ercan I, Cakir BO, Uzel TS, Sakiz D, Karaca C, Turgut S. The role of gastric Heli-cobacter pylori infection in laryngopharyngeal reflux disease. Otolaryngol HeadNeck Surg. 2006;135(1):52-55.

25. Postma GN, Johnson LF, Koufman JA. Treatment of laryngopharyngeal reflux.Ear Nose Throat J. 2002;81(9)(suppl 2):24-26.

26. Ching SS, Sabanathan S, Jenkinson LR. Treatment of Helicobacter pylori in sur-gical practice: a randomised trial of triple versus quadruple therapy in a rural dis-trict general hospital. World J Gastroenterol. 2008;14(24):3855-3860.




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Treatment of Clinically Diagnosed Laryngopharyngeal Reflux Disease