Journal Logo

Research Article: Systematic Review and Meta-Analysis

Efficacy of acid suppression therapy in gastroesophageal reflux disease-related chronic laryngitis

Yang, Yue PhDa,b; Wu, Haitao PhDa,b; Zhou, Jian PhDa,b,*

Editor(s): Kantarçeken., Bülent

Author Information
doi: 10.1097/MD.0000000000004868
  • Open

Abstract

1 Introduction

In the last 2 decades, gastroesophageal reflux disease (GERD)-induced reflux laryngitis has become a familiar finding in ear, nose, and throat symptoms. The proportion of chronic laryngitis (CL) in whole patients visiting to otolaryngology clinics in America was about 10%.[1] Therefore, acid suppression therapy is usually prescribed to these patients under the presupposition that GERD is related with signs and symptoms of CL.[2–4]

It has been revealed that acid suppression improves associated upper esophageal and the gastroesophageal reflux and laryngeal symptoms, for instance, hoarseness and chronic cough.[5] Nevertheless, their efficacy in patients with suspected GERD-related CL has not been definite. GERD-related extraesophageal complications can be controlled efficiently by surgery with a significantly better response than with medicine therapy.[6]

We proceeded this meta-analysis to explore an estimate of the overall efficacy of acid suppression treatment (including medicine therapy and surgery therapy) in suspected GERD-related CL.

2 Methods

2.1 Ethical approval

This is a study of meta-analysis, so that, ethical approval was not necessary.

2.2 Study Search

We proceeded a systematic literature search in PubMed, Web of Knowledge, and Embase for English language article published up till March 2016 by relevant keywords and combinations such as “Proton pump inhibitor,” “antireflux therapy,” “any proton pumps/antagonists & inhibitors,” “H (+)-K (+)-Exchanging ATPase/antagonists & inhibitors,” “rabeprazole,” “histamine H2 antagonists,” “pantaprazole,” “esomeprazole,” “omeprazole,” “lansaprazole,” and “laryngitis,” “pharyngitis,” “reflux laryngitis,” “posterior laryngitis,” “reflux laryngopharyngitis,” “reflux pharyngitis,” “laryngopharyngeal reflux (LPR),” “gastropharyngeal reflux (GPR).” We performed this study according to the guidelines of PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses).

2.3 Data extraction

Suspected GERD-related CL was defined by the occurrence of ≥1 of the following symptoms: hoarseness, globus sensation, excessive phlegm, frequent throat clearing, chronic cough, and the presence of GERD-attributed signs of laryngitis on laryngoscopy-containing erythema, edema, pachydermia, granuloma, or contact ulcer. Adults aged 18 years of age or older with suspected GERD-related CL were entitled for this study.

The data were collected from every eligible article: first author's surname, publication year, country of origin, methods of diagnosis of GERD, and methods of acid suppression therapy separately. All related reports were assessed independently by 2 authors, and based on consensus. We abstracted the proportion of patients who described ≥50% decrease in laryngeal symptoms compared with baseline.

Exclusion criteria were the following: Case reports, review reports, studies not printed in English language; multiple reports providing outcomes from the same research; cohort reports; and animal researches.

2.4 Statistical analysis

The effect size (ES), which is the OOR (%) and 95% confidence interval (95% CI), was assessed for every report. The pooled evaluation of the merged percentage was gotten by the Laid and DerSimonian method in the random effect model. Moreover, we quantified the effect of heterogeneity using I2 = 100% × (Q − df)/Q. A significant I2 statistic (I2 >50%) or Q statistic (P < 0.10) showed heterogeneity across the reports, then the random effects model was used for the meta-analysis.

2.5 Evaluation of publication bias

We calculated the asymmetry of the funnel plot using Begg linear regression and Egger regression test, which evaluated funnel plot asymmetry by means of the natural logarithm scale of the ES. STATA 12.0 (Stata Corporation, College Station, TX) was used in this study.

3 Results

3.1 The characteristics of the eligible reports

There were 253 potential-related reports recognized with the titles, key words, and abstracts. A summary of the study results is shown in Figure 1. There were 54 potentially related full-text studies retrieved for more in-depth assessment after taking out the unrelated reports by assessment of abstract and title. Lastly, 21 separate reports were involved in this meta-analysis. All patients experienced laryngoscopic assessment to make the diagnosis of suspected GERD-related CL with symptoms, for instance, edema, granuloma, erythema, pachydermia, and/or cobblestone pattern, especially in posterior larynx. Ambulatory pH monitoring was carried out in every report, several patients also experienced esophagogastroduodenoscopy and esophageal manometry before enrollment; the primary sources of recruitment of patients in most studies were Otolaryngology clinics.

Figure 1
Figure 1:
Flow diagram.

As is shown in Table 1, 21 reports were involved in the meta-analysis, and the characteristics of the involved reports are displayed. Totally, 2864 patients who suspected GERD-related CL were considered in this meta-analysis.[7–27] The involved reports were published between 1997 and 2013. The sample sizes of the reports were between 8 and 2005. Three studies chose surgical treatment, and the remainder of the studies chose acid suppression medicine treatment.[9,10,12] The duration of proton pump inhibitors (PPIs) treatment ranged from 4 to108 weeks.

Table 1
Table 1:
Characteristics of studies included in this review.

3.2 Overall effects of acid suppression therapy on GERD-related CL

Twenty-one reports that contained a total of 2864 patients were available to assess the ORR of acid suppression therapy (including medicine therapy and surgery therapy) in suspected GERD-related CL. A random-effect model was used on account of significant heterogeneity (I2 = 97.1%, P < 0.01); ORR was 66% (95% CI 54–78%) (Fig. 3).

Figure 3
Figure 3:
Funnel plot to detect publication bias.

3.3 Subgroups analyses

In meta regression (Table 2), there was an obvious discordance between the pooled outcomes for reports performed before 2006 (ORR: 62% [95% CI 50%–74%]) and studies performed from 2006 onwards (ORR: 70% [95% CI 51%–89%]).There was an increase in effect among the pooled outcomes for reports of patients with surgery therapeutic method (ORR: 80% [95% CI: 67%–93%]) relative to studies of patients with medicine therapeutic method (ORR: 64% [95% CI: 50%–77%]) (Table 2). When reports were compared with regard to the duration of treatment (≤8 week and >8 week), response to acid suppression therapy was higher in reports with longer duration of therapy (ORR: 70% [95% CI: 55%– 85%] vs. ORR: 57% [95% CI: 48%–65%]) (Table 2).

Table 2
Table 2:
Sensitivity analysis of subgroup's effect of acid suppression therapy.

3.4 Evaluation of publication bias

No publication bias was obvious in meta-analyses of the association between GERD-related CL and ORR of acid suppression treatment, on the basis of Egger regression test and Begg rank correlation test (Egger test, P = 0.073; Begg test, P = 0.165) (Fig. 2).

Figure 2
Figure 2:
Forest plot for effect of acid suppression success in chronic laryngitis.

4 Discussion

This research is the first study of meta-analysis offering available data on the efficacy of acid suppression therapy in GERD-related CL. Our study confirms formerly published outcomes for ORR in GERD-related CL treated with acid suppression, with ORR of up to 66%.

It is well known that the base for the cure of GERD-related CL in ENT is 8 to 12 weeks’ double-dose PPI.[28] Nevertheless, placebo-controlled studies showed that PPI therapy is no better than placebo in relieving GERD-related laryngopharyngeal symptoms.[29] The assumption for the comparatively poor PPIs response in the researches is a possible selection bias for the reason that GERD diagnosis was not depended on pH-metric standards at all times. Some reports have presented that about 64% to 86% of healthy people could be discovered with laryngeal abnormalities indicative of a laryngeal reflux.[30,31] Therefore, esophageal 24-hour pH watching is required to notarize GERD, particularly as the therapeutic test has not been confirmed for the duration of the ENT clinical situation. El-Serag et al[23] reported that the only predictors of fine effect to PPI were characterized when pathological acid exposure before treatment. Moreover, it is perhaps owing to the point that some patients whose laryngeal symptoms were not caused by GERD would weaken the total study populations leading to reduced power to discover a difference between placebo and PPIs.

There is a popular belief that the result of surgical treatment for reflux is best in typical reflux symptom patients. People with typical reflux symptoms and atypical throat symptoms had a good effect undergoing fundoplication; the result of these patients was similar to that of the bigger group experiencing fundoplication for typical reflux indications without throat discomfort. Farrell et al[32] assessed the ORR in people with typical against atypical symptoms (hoarseness, cough, asthma, and chest pain) after fundoplication. The authors showed that 99% of primarily reflux symptom patients were improved; in addition, 87% patients were entirely cured postoperatively. So et al[33] demonstrated that the treatment of laparoscopic fundoplication had effect on 93% of typical reflux symptoms patients, whereas only 56% atypical symptom patients improved after surgery. The ORR for laryngeal, epigastric/chest pain, and pulmonary was 78%, 48%, and 58%, respectively. Our previous study also indicated that compared to studies of patients with medicine therapeutic method (ORR: 64% [95% CI: 50%–77%]), the effect in the pooled results of patients with surgery therapeutic method was better (ORR: 80% [95% CI: 67%–93%]) (Table 2).

There were some limitations of this study while illustrating the outcomes. First, the heterogeneity in this research is high, which might be rooted in statistical and clinical heterogeneity; the cause might be that the trials are from different districts and the definition of these indicators was not united. Second, a publication bias might lead to the probability of a systematic difference between larger and smaller reports; to be exact, small research possibly overestimated the effects of acid suppression therapy in terms of ORR. Likewise, asymmetry might also root in heterogeneity. Third, comparisons of ORR were hard because of absence of general agreement on the accurate characterization of result and randomization. Last, the reports involved in this study were only printed in English, signifying that a possible language bias occurred.

5 Conclusion

This meta-analysis showed that the overall 1 rate of acid suppression therapy (including medicine therapy and surgery therapy) in suspected GERD-related CL is 66% and there was an increase in effect in the pooled outcomes for the reports of patients who underwent surgery therapeutic method (ORR: 80%) relative to studies of patients with medicine therapeutic method (ORR: 64%); moreover, response to acid suppression therapy was superior to the reports with longer period of therapy (ORR: 70% vs. 57%).

References

1. Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope 1991; 101 (4 Pt 2 Suppl 53):1–78.
2. Koufman J, Sataloff RT, Toohill R. Laryngopharyngeal reflux: consensus conference report. J Voice 1996; 10:215–216.
3. Hanson DG, Jiang JJ. Diagnosis and management of chronic laryngitis associated with reflux. The Am J Med 2000; 108 (Suppl 4a):112s–119s.
4. Vaezi MF, Hicks DM, Abelson TI, et al Laryngeal signs and symptoms and gastroesophageal reflux disease (GERD): a critical assessment of cause and effect association. Clin Gastroenterol Hepatol: the official clinical practice journal of the American Gastroenterological Association 2003; 1:333–344.
5. Katz PO, Castell DO. Medical therapy of supraesophageal gastroesophageal reflux disease. Am J Med 2000; 108 (Suppl 4a):170s–177s.
6. Hinder RA, Branton SA, Floch NR. Surgical therapy for supraesophageal reflux complications of gastroesophageal reflux disease. Am J Med 2000; 108 (suppl 4a):178s–180s.
7. Kirch S, Gegg R, Johns MM, et al Globus pharyngeus: effectiveness of treatment with proton pump inhibitors and gabapentin. Ann Otol 2013; 122:492–495.
8. Wang AJ, Liang MJ, Jiang AY, et al Predictors of acid suppression success in patients with chronic laryngitis. Neurogastroenterol Motil 2012; 24:432–437.e210.
9. Ratnasingam D, Irvine T, Thompson SK, et al Laparoscopic antireflux surgery in patients with throat symptoms: a word of caution. World J Surg 2011; 35:342–348.
10. Salminen P, Karvonen J, Ovaska J. Long-term outcomes after laparoscopic Nissen fundoplication for reflux laryngitis. Digest Surg 2010; 27:509–514.
11. Karoui S, Bibani N, Sahtout S, et al Effect of pantoprazole in patients with chronic laryngitis and pharyngitis related to gastroesophageal reflux disease: clinical, proximal, and distal pH monitoring results. Dis Esophagus 2010; 23:290–295.
12. Salminen P, Sala E, Koskenvuo J, et al Reflux laryngitis: a feasible indication for laparoscopic antireflux surgery? Surg Laparosc Endosc Percutan Techn 2007; 17:73–78.
13. Qua CS, Wong CH, Gopala K, et al Gastro-oesophageal reflux disease in chronic laryngitis: prevalence and response to acid-suppressive therapy. Aliment Pharmacol Ther 2007; 25:287–295.
14. Dore MP, Pedroni A, Pes GM, et al Effect of antisecretory therapy on atypical symptoms in gastroesophageal reflux disease. Dig Dis Sc 2007; 52:463–468.
15. Monini S, Di Stadio A, Vestri A, et al Silent reflux: ex juvantibus criteria for diagnosis and treatment of laryngeal disorders. Acta Otolaryngol 2006; 126:866–871.
16. Ahmed TF, Khandwala F, Abelson TI, et al Chronic laryngitis associated with gastroesophageal reflux: prospective assessment of differences in practice patterns between gastroenterologists and ENT physicians. Am J Gastroenterol 2006; 101:470–478.
17. Vaezi MF, Richter JE, Stasney CR, et al Treatment of chronic posterior laryngitis with esomeprazole. Laryngoscope 2006; 116:254–260.
18. Wo JM, Koopman J, Harrell SP, et al Double-blind, placebo-controlled trial with single-dose pantoprazole for laryngopharyngeal reflux. Am J Gastroenterol 2006; 101:1972–1978.quiz 2169.
19. Steward DL, Wilson KM, Kelly DH, et al Proton pump inhibitor therapy for chronic laryngo-pharyngitis: a randomized placebo-control trial. Otolaryngol Head Neck Surg 2004; 131:342–350.
20. Eherer AJ, Habermann W, Hammer HF, et al Effect of pantoprazole on the course of reflux-associated laryngitis: a placebo-controlled double-blind crossover study. Scand J Gastroenterol 2003; 38:462–467.
21. Ulualp SO, Toohill RJ, Shaker R. Outcomes of acid suppressive therapy in patients with posterior laryngitis. Otolaryngology Head Neck Surg 2001; 124:16–22.
22. Hamdan AL, Sharara AI, Younes A, et al Effect of aggressive therapy on laryngeal symptoms and voice characteristics in patients with gastroesophageal reflux. Acta Otolaryngol 2001; 121:868–872.
23. El-Serag HB, Lee P, Buchner A, et al Lansoprazole treatment of patients with chronic idiopathic laryngitis: a placebo-controlled trial. Am J Gastroenterol 2001; 96:979–983.
24. Noordzij JP, Khidr A, Evans BA, et al Evaluation of omeprazole in the treatment of reflux laryngitis: a prospective, placebo-controlled, randomized, double-blind study. Laryngoscope 2001; 111:2147–2151.
25. Langevin S, Ngo H. GERD-induced ENT symptoms: A prospective placebo controlled study with omeprazole 40 mg a day. Gastroenterology 2001; 120:A16–A116.
26. Havas T, Huang S, Levy M, et al Posterior pharyngolaryngitis. Double-blind randomised placebo-controlled trial of proton pump inhibitor therapy. Australian J Otolaryngol 1999; 3:243–246.
27. Wo JM, Grist WJ, Gussack G, et al Empiric trial of high-dose omeprazole in patients with posterior laryngitis: a prospective study. Am J Gastroenterol 1997; 92:2160–2165.
28. Vallot T, Carella G. Medical treatment of gastroesophageal reflux with proton pump inhibitors. Gastroenterol Clin Biologique 1999; 23 (1 pt 2):S97–S109.
29. Qadeer MA, Phillips CO, Lopez AR, et al Proton pump inhibitor therapy for suspected GERD-related chronic laryngitis: a meta-analysis of randomized controlled trials. Am J Gastroenterol 2006; 101:2646–2654.
30. Reulbach TR, Belafsky PC, Blalock PD, et al Occult laryngeal pathology in a community-based cohort. Otolaryngol Head Neck Surg 2001; 124:448–450.
31. Hicks DM, Ours TM, Abelson TI, et al The prevalence of hypopharynx findings associated with gastroesophageal reflux in normal volunteers. J Voice 2002; 16:564–579.
32. Farrell TM, Richardson WS, Trus TL, et al Response of atypical symptoms of gastro-oesophageal reflux to antireflux surgery. Br J Surg 2001; 88:1649–1652.
33. So JB, Zeitels SM, Rattner DW. Outcomes of atypical symptoms attributed to gastroesophageal reflux treated by laparoscopic fundoplication. Surgery 1998; 124:28–32.
Keywords:

antireflux surgery; chronic laryngitis; GERD; laryngopharyngeal reflux; meta-analysis; pharyngitis; proton pump inhibitor

Copyright © 2016 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.