Periodontal therapy as adjunctive treatment for gastric Helicobacter pylori infection
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective is to determine whether periodontal therapy is a useful adjunctive treatment for gastric H. pylori infection. Specifically, the primary aim is to compare the relative efficacy of periodontal therapy plus triple eradication therapy with triple eradication therapy alone in the treatment of gastric H. pylori infection by reviewing current RCTs.
The secondary objective is to compare the recurrence rate of gastric H. pylori infection after successful eradication in different treatments.
Background
Description of the condition
The prevalence of Helicobacter pylori (H. pylori) is estimated to affect about half the world's population, possibly reaching up to 70% to 90% in developing countries and 25% to 50% in developed countries (Go 2002). Of all individuals infected with H. pylori, only a small percentage develops related diseases. Diseases associated with H.pylori infection commonly happen at earlier ages in developing countries (Balaban 1997). This is probably due to various host‐related factors, the difference in strains of H. pylori, and the duration of infection and environmental factors, including socioeconomic status (Yamaoka 2010). H. pylori infection is considered as the major cause of chronic gastritis and peptic ulcer disease (Suerbaum 2002). Most individuals infected H. pylori have the presence of gastritis. Many of them are never diagnosed because they have so few or no symptoms. About 10% to 20% of them will develop gastric and duodenal ulcer. The duodenal ulcer was much more prevalent than gastric ulcer disease (Schlemper 1996). A paper from Serbia showed duodenal ulcer was found in 15% to 25% and gastric ulcer in 13% (Sokić‐Milutinović 2004). H. pylori is also linked with gastric adenocarcinoma and mucosa‐associated lymphoid tissue lymphoma. H. pylori‐positive individual has a less than 3% lifetime risk of developing adenocarcinoma and a 1% risk of developing MALT lymphoma (Balaban 1997; Peek 2002; Kusters 2006). Eradication of H. pylori infection accelerates ulcer healing and prevents relapse, and reduce incidence of H. pylori‐related gastric diseases (Graham 1991; Hopkins 1996; Kim 1998; Tytgat 1994).
Description of the intervention
Triple therapy, including a proton pump inhibitor (PPI) plus two antibiotics, such as clarithromycin and amoxycillin or metronidazole, is the most common first‐line intervention regimen clinically (Asaka 2001; Hunt 1999; Shirin 2004; Wolle 2007). Taking into account the high prevalence of clarithromycin resistance, quadruple therapy (PPI+bismuth+metronidazole+tetracycline) is used as an alternate strategy. In recent years, sequential therapy (agents are administered in sequence) and concomitant therapy (non‐bismuth quadruple therapy) have also been reported as alternatives. Eradication rates in these alternative strategies have been reported as similar to PPI‐triple therapy. In fact, however, the results of recent studies have shown that eradication rates have been documented at the lowest level in the past decade (Vakil 2009). This could be due to incomplete elimination of H. pylori, leading to recurrence (Xia 1997). Generally, the recurrence rate of H. pylori in developing countries was about 13.00%, while in developed countries it was 2.67% (Niv 2008). Recurrence is more frequent in developing countries, with one report indicating that the recurrence rate in India has been documented as high as 40% (Rimbara 2011). The causes seem to be the limitations of hygiene, and socioeconomic constraints. It has been demonstrated that recurrence of H. pylori is due to either recrudescence of the same strain or reinfection with a new strain. Recrudescence is more common than reinfection (Gisbert 2006; Xia 1997).
How the intervention might work
It is critical to identify factors contributing to the recrudescence of gastric H. pylori. Apart from the stomach, H.pylori also has been found in the distal esophagus, the proximal duodenum, the colonic contents, and the oral cavity, including tonsil and adenoid tissue (Cover 2009; Eyigor 2009). Considerable research has been published on the relationship between oral cavity and gastric H. pylori infection. Numerous studies have provided evidence that the oral cavity may be a potential reservoir for H. pylori. H. pylori has been detected in saliva, dental plaques, and gingival pockets (Pytko‐Polonczyk 1996; Song 2000; Dowsett 2003; Gebara 2006; Burgers 2008; Liu 2009). Conversely, other investigators have indicated that the oral cavity may not be a reservoir of H. pylori (Olivier 2006; Silva Rossi‐Aguiar 2009). This contention is largely based upon different detection methods for oral H. pylori, compounded by the fact that there are several types of urease‐producing bacteria in the mouth including Streptococcus, Haemophilus species, and Actinomyces species. The test based on urease activity is not applicable for diagnosis; culture is a more sensitive method. However, culture is difficult to gather successfully due to the potential for formation of a viable coccoid (Chaudhry 2008). Currently, polymerase chain reaction (PCR) is the most effective method for testing oral H. pylori in clinical settings with high sensitivity and specificity. The specificity depends on the different sets of primers (Song 1999; Song 2000). A meta‐analysis published in 2011 reported a strong connection between the presence of H. pylori in the oral cavity and that in the stomach (Zou 2011): between 39.5% and 64% of patients with gastric H. pylori also have oral H.pylori. In contrast, H. pylori has been detected in gastric samples in 83.3% of patients with oral H. pylori (Song 2000; Medina 2010). However, triple eradication therapy has no or little effect on elimination of oral H. pylori; eradication rates for oral infection have been recorded below 40% (Miyabayashi 2000; Gebara 2006; Czesnikiewicz‐Guzik 2007). The presence of oral H. pylori might affect the effect of eradication therapy and act as a causal element in the recurrence of H. pylori infection. Furthermore, Sheu and colleagues have proposed that the presence of dental disease could predispose the patients to recurrent H. pylori infection after successful eradication (Sheu 2007).
Considering the important role of the oral cavity in gastric H. pylori infection, periodontal therapy, including oral hygiene procedures, and dental plaque and dental calculus control measures, has been considered as adjunctive treatment for gastric H. pylori infection (Namiot 2007; Jia 2009; Zaric 2009).
Why it is important to do this review
It is important to clarify whether periodontal therapy is an effective adjunctive treatment for gastric H. pylori infection. Therefore, it is necessary to perform a meta‐analysis to evaluate the effectiveness of periodontal therapy in eradication of gastric H. pylori infection on the basis of current randomized controlled trials (RCTs) in order to understand the available data more comprehensively.
Objectives
The objective is to determine whether periodontal therapy is a useful adjunctive treatment for gastric H. pylori infection. Specifically, the primary aim is to compare the relative efficacy of periodontal therapy plus triple eradication therapy with triple eradication therapy alone in the treatment of gastric H. pylori infection by reviewing current RCTs.
The secondary objective is to compare the recurrence rate of gastric H. pylori infection after successful eradication in different treatments.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCTs) comparing periodontal therapy plus triple therapy with triple therapy alone. We will exclude trials examining dual therapy (PPI+ antibiotic) because of the disappointing efficacy.
Types of participants
Adults objectively diagnosed as positive for gastric H. pylori will be eligible for inclusion, with or without oral H. pylori infection. The gastric H. pylori positive was assessed by serology, rapid urease test (RUT), histology or culture of endoscopic antral/body biopsy specimens, or urea breath test (UBT). The sensitivity and specificity of these methods are similar (Ricci 2007). For this meta‐analysis, the participants will be diagnosed as gastric H.pylori‐positive with at least one positive result of above tests. For oral H. pylori, the PCR analysis will be used to gain accurate result.
We will exclude studies that included patients that had received any eradication treatment of H. pylori infection within four weeks prior to the study.
Types of interventions
We will include all RCTs which used periodontal therapy combined with eradication therapy for the treatment of gastric H. pylori infection, regardless of the H. pylori eradication regimens. Periodontal therapy considered for this review comprises oral hygiene training, removal of supragingival and accessible subgingival bacterial plaque and calculus by periodontal scaling, periodontal root planing and chemotherapeutic agents (e.g., irrigation of periodontal pockets). However, we will exclude trials with oral surgical treatment. Periodontal therapy will be started at the beginning of eradication therapy.
Types of outcome measures
Primary outcomes
Eradication rate of gastric H. pylori. (We will assess eradication at four weeks after therapy. The negative result of H. pylori will be confirmed by UBT mainly. The successful eradication will also be defined when the result is negative in the test of serology, RUT, histology or culture of an endoscopic antral/body biopsy specimen.)
Secondary outcomes
Recurrence rate of gastric H. pylori (at least 6 months after eradication therapy).
Search methods for identification of studies
We will conduct searches to identify all published and unpublished trials for this review. We will not apply any language restrictions.
Electronic searches
We will identify trials by searching the following electric databases.
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The Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) Appendix 1.
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MEDLINE Appendix 2.
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EMBASE Appendix 3.
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Chinese Biomedical Database.
Searching other resources
We will handsearch to identify relevant trials from the reference list of each selected article. We will also search reference lists of abstracts from all relevant meetings proceedings.
Data collection and analysis
Selection of studies
We will identify related trials by performing computer assisted bibliographic database search and hand search. In order to determine the included studies, two review authors will independently review abstracts from relevant trails using pre‐designed inclusion criteria. If we cannot include or exclude an article solely on the basis of the abstract, we will review the article in full. A third author will decide whether an article could be included when there is any disagreement.
Data extraction and management
Two authors will independently extract details of each study using a pre‐defined data collection form. We will record the study design, participants, setting and timing, interventions, patient characteristics, and outcomes, etc. in as much detail as possible. We will resolve disagreements by consultation with the senior author. We will also input outcome data in an Excel database for checking potential input errors.
Assessment of risk of bias in included studies
Two review authors will independently assess the methodological quality of each study in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The senior author will participate in resolving discrepancies in order to reach a consensus.
We will assess trials according to the following criteria.
Was the allocation sequence adequately generated?
We will assess the allocation sequence as truly random, unclear, or not stated. We will define 'truly random' as: computer generated random numbers, published random number table, coin toss, shuffled card, etc.
Was allocation adequately concealed?
We will assess allocation concealment as adequate, inadequate, or unclear.
We will define adequate concealment as follows: trialists are ignorant of the allocation of each recruited participant when they are entered in the study. Methods such as central randomization schemes, pharmacy‐based schemes, opaque sealed envelopes, etc.
Was knowledge of the allocated interventions adequately prevented during the study?
We will assess prevention of knowledge as triple blind, double blind, single blind, not blinded, or unclear.
If the patients, investigator and outcome assessors are not aware of the treatments, we will define the trial as "triple blind".
If two of them are not aware of the treatments, we will define the trial as "double blind".
If only one is not aware of the treatments, we will define the trial as "single blind".
We will judge trails as blinded, not blinded, or unclear on the basis of the available information.
Were incomplete outcome data adequately addressed?
We will note the completeness of follow‐up and whether the intention to treat analysis is reported.
Measures of treatment effect
We will calculate the odds ratio to perform data analysis for evaluating the eradication rate of H. pylori and the recurrence rate of gastric H. pylori infection.
Dealing with missing data
We will try to contact the authors of original RCTs for missing information. We will calculate the outcome with the intention‐to‐treat analytical approach. We will consider the dropouts as individuals of treatment failure.
Assessment of heterogeneity
We will assess statistical heterogeneity with the Chi2 test with significance set at P value 0.10. We will measure the quantity of heterogeneity using I2 statistic (Higgins 2002). We will judge I2 greater than 25% as heterogeneity. We will consider clinical heterogeneity and the heterogeneity of study quality.
Assessment of reporting biases
According to the number of included trails, we will determine whether it is necessary to prepare a funnel plot for assessing publication bias (Egger 1997).
Data synthesis
We will use Review Manager software (RevMan 2011) to pool and analyze the trials' data and use forest plots to exhibit the results of this meta‐analysis. All data are dichotomous outcomes. We will express the results as the odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs). We will pool data using both fixed‐effect and random‐effects models. We will only report the results of fixed‐effect models if we find no significant difference. Otherwise we will report the results from fixed‐effect and random‐effects models.
Subgroup analysis and investigation of heterogeneity
We plan to conduct subgroup analysis based on the participants with or without oral H. pylori infection, regardless of the type and the duration of PPIs and antibiotics.
We will also carry out subgroup analysis based on the different durations of periodontal therapy:
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during eradication therapy only;
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continued until testing the result of eradication therapy is complete (four weeks after eradication therapy);
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continued for longer (more than four weeks after eradication therapy).
We will also perform subgroup analysis on the basis of different levels of economic development (developed countries or developing countries) and whether or not the patients were diagnosed with periodontitis and prescribed periodontal therapy.
Sensitivity analysis
We will conduct sensitivity analysis by removing trials which were not analyzed using ITT to check how robust the results are. We will also perform sensitivity analysis according to relevant clinical features. If we find there are low‐quality studies in meta‐analysis, we will conduct sensitivity analysis to determine whether the pooled results are steady. We will assess the quality of included studies by modified Jadad scale. We will define the studies as low quality with less than four points.
