1. Introduction
Gastroesophageal reflux disease (GERD), is a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications.[1,2] GERD patients have a high prevalence of airway symptoms, such as chronic cough, croup, hoarseness, and wheezing.[3,4] Gastroesophageal reflux-related cough (GERC), is one common type of chronic cough, accounting for about 20% of all kinds of chronic cough.[5] Several potential mechanisms of GERC have been addressed, though the evidence is limited. The first mechanism is the esophageal-bronchial reflex.[5] The irritated esophagus activates the vagus nerve, resulting in reflex cough.[6] The second mechanism is microaspiration. Tiny gastric contents regurgitate into the airway, inducing cough.[7,8] The third mechanism is laryngopharyngeal reflux, a cough caused by reflux into the throat.[9,10]
In the treatment of GERC, drug therapy is the first line.[11] Proton pump inhibitor (PPI) is recommended to take for at least 8 weeks.[11,12] Besides, prokinetic agents and neuroregulator are also recommended.[13,14] Drug treatment is effective for some GERC patients. But, there are refractory GERC (rGERC) patients. For rGERC patients, drug treatment is not effective, and the drug treatment includes at least 8 weeks of adequate PPI therapy.[15] For rGERC patients, surgical operation, mainly fundoplication, may be the only effective method. But in the treatment of rGERC, the importance of fundoplication is underrated and poorly studied. In theory, fundoplication can heal all types of reflux. However, the causes of rGERC are various, and the actual conditions of rGERC are complicated, and patients benefit differently from fundoplication, so the cure rate of fundoplication in treating rGERC could not reach 100%. Hence, there is a question, what is the cure rate of fundoplication in treating rGERC? There are very few systematic reviews and meta-analyses looking into this question, and the cure rate of fundoplication in treating rGERC is unknown. To solve this question, we performed this meta-analysis. The definition of “cure” is that the symptom of chronic cough disappears completely.
2. Methods
2.1. Protocol register
The PRISMA strategy and Cochrane collaboration method were used for this study.[16,17] This study was registered in PROSPERO (http://www.crd.york.ac.uk/PROSPERO), an international prospective register of systematic reviews, in April 2021 (Registration ID: CRD42021251072). Literature review and analysis were completed through February 2023.
2.2. Literature selection
We searched PubMed, Medline, Web of Science, and the Cochrane databases from 1990 to December of 2022 using the search terms: gastroesophageal reflux OR GERD OR reflux OR gastroesophageal reflux disease OR reflux esophagitis, cough OR coughs OR chronic cough OR chronic coughs, and fundoplication OR Nissen operation OR Toupet operation OR surgical procedures OR surgery.
2.3. Diagnosis of GERC
The diagnostic criteria of GERC included esophageal 24-h pH monitoring, acid exposure time > 6%, and symptom association probability > 95%; after anti-reflux therapy, symptom of cough improving significantly.[13,14]
2.4. Assessment of cough symptom
Assessment of cough was scored by cough scales. Cough scales include visual analog scales, Leicester cough questionnaire, cough-specific quality of life questionnaire, etc.[1,2,13]
2.5. Selection and exclusion criteria
Inclusion criteria were as follows: objects of studies were adults or children; clear diagnosis of GERC; certain of drug treatment failure; therapy method was laparoscopic fundoplication. Exclusion criteria were as follows: case reports, review, and animal experiments; patients of studies had primary lung disease; unclear diagnosis of GERC; not certain of drug treatment failure; therapy method included other surgical operation (such as endoscope radiofrequency and endoscope band ligation).
2.6. Data extraction and quality assessment
Two reviewers, blinded to authors’ names, journals, and year of publication of the literature, independently reviewed literature searches, selected articles, and extracted data. Disagreement was resolved through consensus or by consulting a third reviewer. We used the k statistic to assess agreement between reviewers. We combined data with parallel studies, and the data from the first arm of crossover trials were used. Newcastle–Ottawa scale was used for article quality evaluation.[18]
2.7. Statistical analysis
The analysis was performed with Review Manager 5.4 (The Nordic Cochrane Centre, Copenhagen, Denmark) and Stata 14 (StataCorp LP, College Station, TX). Data were pooled using fixed effects model. Heterogeneity was assessed by I2 statistic and P value of X2. I2 <50% and P value > 0.1 were considered as no statistically significant heterogeneity. Publication bias was assessed by Egger test of funnel plots. P value > 0.05 of Egger test was considered as no statistically significant bias.
3. Results
3.1. Study selection and characteristics
The search strategy identified 672 citations. From these, 62 articles were considered relevant to our study and eventually, there were 8 articles that fulfilled the eligibility criteria (Fig. 1).[19–26] The 8 studies included 503 patients, and no deaths were reported. Agreement between reviewers for assessment of article eligibility was good (k statistic = 0.96).[16] Detailed characteristics of all included studies were shown in Table 1.
Table 1 -
Detailed characteristics of 8 included studies.
| Author and year |
Type of study |
Study population |
No. of patients |
No. of non-cough after surgery |
Postoperative follow-up time |
Allen
1997 |
Prospective |
Adults |
62 |
30 |
6 mo |
Marco
2000 |
Retrospective |
Adults |
39 |
29 |
3 mo |
Novitsky
2001 |
Retrospective |
Adults |
21 |
13 |
2 mo |
Allen
2003 |
Retrospective |
Adults |
209 |
109 |
6 mo |
Kirkby
2010 |
Retrospective |
Adults |
21 |
13 |
3 mo |
Oliver
2011 |
Prospective |
Adults |
90 |
72 |
3 mo |
Ciro
2018 |
Retrospective |
Children |
20 |
18 |
3 mo |
Tamara
2019 |
Retrospective |
Adults |
41 |
27 |
1.5 mo |
;)
Figure 1.: Details of included and excluded studies.
3.2. Article quality evaluation
Of the 8 articles, 6 were retrospective cohort studies, and 2 were prospective studies. In Newcastle–Ottawa scale, the scores of 8 articles were 5 or 6, total score = 9 (Table 2). Newcastle–Ottawa scale showed that there were no obvious problems in the 8 articles in experimental design, experimental procedure, outcome assessment, and follow-up. However, our confidence in our study was general, not very much, because most of the studies were retrospective.
Table 2 -
Quality assessment of 8 studies by Newcastle–Ottawa scale.
|
Selection (1 score for each item) |
Comparability study controls for confounders (2 scores) |
Outcomes (1 score for each item) |
|
| Author and year |
Adequacy of definition |
Diagnosis of medical treatment failed GERC |
Representativeness of cases |
Selection of controls |
Assessment of outcome |
Follow-up long enough for outcomes to occur |
Adequacy of follow-up of cohorts |
Total |
Allen
1997 |
1 |
1 |
1 |
0 |
0 |
1 |
1 |
1 |
6 |
| Marco 2000 |
1 |
1 |
1 |
0 |
0 |
1 |
1 |
1 |
6 |
| Novitsky 2001 |
1 |
1 |
0 |
0 |
0 |
1 |
1 |
1 |
5 |
Allen
2003 |
1 |
1 |
1 |
0 |
0 |
1 |
1 |
1 |
6 |
| Kirkby 2010 |
1 |
1 |
0 |
0 |
0 |
1 |
1 |
1 |
5 |
Oliver
2011 |
1 |
0 |
1 |
0 |
0 |
1 |
1 |
1 |
5 |
Ciro
2018 |
1 |
1 |
0 |
0 |
0 |
1 |
1 |
1 |
5 |
| Tamara 2019 |
1 |
1 |
1 |
0 |
0 |
1 |
1 |
1 |
6 |
GERC = gastroesophageal reflux-related chronic cough.
3.3. Meta-analysis and subgroup analysis
When pooling data from the 8 studies, the meta-analysis showed that the cure rate of laparoscopic fundoplication in treating rGERC was 62% (95% confidence interval [CI]: 53–71%), which meant that fundoplication could completely heal two-thirds of rGERC patients. Detailed characteristics of the meta-analysis were shown in Figure 2. The heterogeneity of the meta-analysis was very low, with P value = 0.30 > 0.1, and I2 = 17% < 50%, which meant that there was no significant heterogeneity in the meta-analysis. In Egger test of funnel plots, P value = 0.227 > 0.05, which meant that there was no significant bias in our meta-analysis.
Figure 2.: Meta-analysis of the cure rate of laparoscopic fundoplication in treating rGERC. rGERC = refractory gastroesophageal reflux-related chronic cough.
In the subgroup meta-analysis of the 7 articles about adult patients, the cure rate of laparoscopic fundoplication in treating rGERC was 61% (95% CI: 52–70%). Detailed characteristics were shown in Figure 3.
Figure 3.: Subgroup meta-analysis of the cure rate of laparoscopic fundoplication in treating rGERC of adult patients. rGERC = refractory gastroesophageal reflux-related chronic cough.
In the subgroup meta-analysis by time, the cure rate of laparoscopic fundoplication in treating rGERC was 76% (95% CI: 61–90%) in articles after 2010, while the cure rate was 55% (95% CI: 44–65%) in articles prior to 2010. Detailed characteristics were shown in Figure 4.
Figure 4.: Subgroup meta-analysis of the cure rates of laparoscopic fundoplication in treating rGERC compared by time. rGERC = refractory gastroesophageal reflux-related chronic cough.
There were 4 articles in which patients had no evident improvement in cough even after the maximum dose of PPI treatment (omeprazole 80 mg/day). In the subgroup meta-analysis of these 4 articles, the cure rate of laparoscopic fundoplication in treating rGERC was 53% (95% CI: 42–64%). Detailed characteristics were shown in Figure 5.
Figure 5.: Subgroup meta-analysis of the cure rate of laparoscopic fundoplication in treating rGERC patients after maximum dose PPI treatment failure. PPI = proton pump inhibitor, rGERC = refractory gastroesophageal reflux-related chronic cough.
4. Discussion
The meta-analysis showed that the cure rate of laparoscopic fundoplication in treating rGERC was 62%. However, there remained 38% of patients who had not been cured by fundoplication, which suggested that when the goal was to cure rGERC, perhaps we should take a relatively conservative attitude to fundoplication. In another study of ours that had not been published yet, the response rate of fundoplication (symptomatic relief > 50%), not cure rate, was from 82 to 100%, which meant that when rGERC seriously affected the quality of life and the requirement of treatment effect was not too high, laparoscopic fundoplication was a good option.
The cure rates of 7 articles about adults were from 48 to 80%, and the subgroup meta-analysis of 7 articles about adults showed that the cure rate of laparoscopic fundoplication in treating rGERC was 61% (95% CI: 52–70%), very close to the total cure rate 62% (95% CI: 53–71%).
In the subgroup meta-analysis by time, the cure rate of laparoscopic fundoplication in treating rGERC was 76% in articles after 2010, while the cure rate was 55% in articles prior to 2010. The reason is complicated and may be related to many factors, such as improved surgical technique, bias in different medical centers, and patient selection.
There were 4 articles in which patients had no evident improvement in cough even after maximum dose of PPI treatment (omeprazole 80 mg/day). In the subgroup meta-analysis of the 4 articles, the cure rate of laparoscopic fundoplication in treating rGERC was 53%, lower than the average, which indicates that the curative effect of laparoscopic fundoplication might not be very good for patients after maximum dose PPI treatment failure.
The cause of GERC is not an overproduction of stomach acid. At present, PPI therapy as the main method of GERC treatment is only a stopgap measure, which can not resolve the essential problem. For some patients, the essence of rGERC is the decreased anti-reflux barrier function of esophagogastric junction.[13] So, repairing anti-reflux anatomy structure is the fundamental method for treating rGERC, and in some ways, rGERC is essentially a surgical disease.[1,13]
A number of studies have found that the frequency of weak acid reflux and alkaline reflux in rGERC patients is significantly higher than that in normal GERC patients, which indicates that weak acid reflux and alkaline reflux may be important causes of rGERC.[21,27,28] However, drug treatment has a good effect on acid reflux (PH < 4), but a poor effect on weak acid reflux (4 < PH < 7) and alkaline reflux (PH > 7).[29,30] For these patients, laparoscopic fundoplication may be a good treatment choice. The disadvantages of surgery are invasive and risky, although fundoplication has been proven to be quite a safety offered by appropriately skilled surgeons.[27,30]
The cure rate of fundoplication for typical GERD symptoms such as reflux and heartburn is 85 to 100%.[1,2,13] It could be seen that fundoplication for GERC is less effective than fundoplication for typical GERD symptoms. This may be related to the complexity of GERC. In one case, the diagnosis of GERC is incorrect. The cough is not caused by GERD but caused by other factors, which is not identified before surgery. Other reflux symptoms may be significantly relieved after surgery, but cough is naturally difficult to relieve. In another case, cough is caused by other factors, and GERD is a factor that exacerbates cough. The reflux is controlled after surgery, and the cough will be relieved, but it will not be cured, because the real cause of the cough has not been eliminated.
Our study has several limitations. First, in our meta-analysis, most of the studies were retrospective, which means the evidence level of our meta-analysis is not high. Second, in our meta-analysis, there are 8 studies included, and the number of total patients is 503, both of which are not very large. Third, of the 8 studies, only 1 study is about children, so the data on children are insufficient and unpersuasive.
In conclusion, this meta-analysis has found that the cure rate of laparoscopic fundoplication in treating rGERC is 62%, with no deaths in 503 patients. In terms of safety, laparoscopic fundoplication is quite reliable offered by skilled surgeons. In terms of cure rate for rGERC, laparoscopic fundoplication is effective for some patients; however, a relatively conservative attitude should be taken, because there are still some patients who can not get cured from fundoplication.
Author contributions
Conceptualization: Jiannan Liu，Jimin Wu
Data curation: Jiannan Liu, Changrong Deng, Meiguang Zhang.
Formal analysis: Zhiwei Hu, Yu Zhang.
Investigation: Jimin Wu, Minjie Sun.
Methodology: Jiannan Liu, Changrong Deng.
Project administration: Jimin Wu, Meiguang Zhang.
Resources: Yu Zhang, Meiguang Zhang.
Software: Jiannan Liu, Zhiwei Hu.
Supervision: Changrong Deng, Minjie Sun.
Validation: Zhiwei Hu, Yu Zhang.
Writing – original draft: Jiannan Liu, Changrong Deng, Yu Zhang
Writing – review & editing: Jimin Wu, Meiguang Zhang.
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