|Year : 2009 | Volume
| Issue : 2 | Page : 206-211
|Helicobacter pylori coinfection is a confounder, modulating mucosal inflammation in oral submucous fibrosis
R Rajendran1, R Rajeev2, S Anil1, Mohammed Alasqah1, Abdul Gafoor Rabi3
1 King Saud University College of Dentistry, Riyadh, Saudi Arabia
2 Government Dental College, University of Kerala, India
3 King Khalid Hospital, Riyadh, Saudi Arabia
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|Date of Submission||28-Nov-2008|
|Date of Decision||20-Feb-2009|
|Date of Acceptance||03-Jun-2009|
|Date of Web Publication||23-Jun-2009|
| Abstract|| |
The oral cavity has been considered a potential reservoir for Helicobacter pylori (H pylori) , from where the organism causes recurrent gastric infections. Aim: With this case-control study we tried to evaluate the role of H pylori in the etiology of mucosal inflammation, a condition that compounds the morbid state associated with oral submucous fibrosis (OSF). Materials and Methods : Subjects ( n = 150) were selected following institutional regulations on sample collection and grouped into test cases and positive and negative controls based on the presence of mucosal fibrosis and inflammation. The negative controls had none of the clinical signs. All patients underwent an oral examination as well as tests to assess oral hygiene/periodontal disease status; a rapid urease test (RUT) of plaque samples was also done to estimate the H pylori bacterial load. We used univariate and mutivariate logistic regression for statistical analysis of the data and calculated the odds ratios to assess the risk posed by the different variables. Results : The RUT results differed significantly between the groups, reflecting the variations in the bacterial loads in each category. The test was positive in 52% in the positive controls (where nonspecific inflammation of oral mucosa was seen unassociated with fibrosis), in 46% of the test cases, and in 18% of the negative controls (healthy volunteers) (χ2 = 13.887; P < 0.01). A positive correlation was seen between the oral hygiene/periodontal disease indices and RUT reactivity in all the three groups. Conclusions: The contribution of the H pylori in dental plaque to mucosal inflammation and periodontal disease was significant. Logistic regression analysis showed gastrointestinal disease and poor oral hygiene as being the greatest risk factors for bacterial colonization, irrespective of the subject groups. A positive correlation exists between RUT reactivity and the frequency of mucosal inflammation.
Keywords: Dental plaque, morbidity, oral inflammation, oral submucous fibrosis, rapid urease test
|How to cite this article:|
Rajendran R, Rajeev R, Anil S, Alasqah M, Rabi AG. Helicobacter pylori coinfection is a confounder, modulating mucosal inflammation in oral submucous fibrosis. Indian J Dent Res 2009;20:206-11
Oral submucous fibrosis (OSF) is consistently associated with mucosal inflammation of the upper aero-digestive tract, mainly manifesting as stomatitis and glossitis.  This mucosal inflammation contributes to the morbidity and the clinical symptoms of the disorder. In OSF, as the disease advances, there is progressive limitation of mouth opening and tongue protrusion, which is partly attributable to the chronic inflammation of the oral mucosa and the resultant scarring. It is reasonable to assume that these two reactive tissue responses, viz, inflammation and scarring, together determine the extent of interference with oral functions.  The bacterial load, reflected by the poor oral hygiene status and periodontal health, is mainly responsible for maintaining this heightened state of mucosal inflammation, as it is elsewhere in the gastrointestinal tract. Helicobactor pylori (H. pylori) infection is one of the most common bacterial infections in man.  The infection is widely accepted to be an important cause of gastritis and is strongly associated with peptic ulcer disease (PUD) and gastric cancer.  Despite numerous studies, the hypothesis that the oral flora may be a permanent reservoir of viable H. pylori is still controversial. , Once colonization is established, the microflora at a site remains relatively stable over time despite regular minor perturbations in the oral environment.  Dental plaque has been implicated as a potential reservoir of H. pylori, and the organism has also been detected in saliva. ,, This study was undertaken to determine the H. pylori bacterial load in OSF patients in whom there is persistent clinically detectable mucosal inflammation and to compare it with the bacterial load in patients with similar mucosal states (but without oral fibrosis) and also with that in healthy volunteers. We examined the correlation between the bacterial load and the frequency and severity of inflammation, which has got a direct significance in overall disease management. We discuss the role played by this organism in accentuating the morbid state associated with OSF. We feel that eradication of H. pylori from dental plaque should be made an important part of the comprehensive management of H. pylori-associated oral mucositis, a feature consistently seen in OSF.
|How to cite this URL:|
Rajendran R, Rajeev R, Anil S, Alasqah M, Rabi AG. Helicobacter pylori coinfection is a confounder, modulating mucosal inflammation in oral submucous fibrosis. Indian J Dent Res [serial online] 2009 [cited 2019 Apr 25];20:206-11. Available from: http://www.ijdr.in/text.asp?2009/20/2/206/52898
| Materials and Methods|| |
This case-control study was carried out at the Department of Oral Pathology and Microbiology, Government Dental College, Trivandrum, after obtaining approval from the concerned ethics committee. Fifty histologically proven cases of OSF (M: F = 17: 33) with evidence of oral mucosal inflammation (stomatitis and glossitis) comprised the test cases. Fifty patients (M: F = 25:25) with clinically detectable mucosal inflammation of a persistent nature, but without evidence of oral fibrosis, constituted the positive controls. Another 50 age- and sex-matched healthy volunteers (M: F = 27:23), without oral fibrosis and/or mucosal inflammation, served as the negative controls for this study. We used a structured questionnaire to collect data on the following variables:
- Sociodemographic variables
- Systemic diseases, including gastrointestinal diseases
- Oral hygiene (as per the Greene and Vermillion index)  and periodontal disease status [as per the 3 rd National Health and Nutrition Examination Survey (NHANES III) criteria] 
Written informed consent was obtained from all subjects who participated in the study. Oral examination included assessment of oral hygiene status, periodontal disease status, and examination of plaque for H. pylori using the rapid urease test (RUT). Oral hygiene status was assessed and categorized as 'good,' 'fair,' and 'poor,' using the oral hygiene index of Greene and Vermillion.  Periodontal status was assessed based on the criteria established by NHANES III. Patients having one or more sites with a probing depth ≥ 3 mm and clinical attachment loss ≥ 3 mm at the same site(s) were classified as having periodontal disease. Presence of H. pylori in the dental plaque was determined using the RUT. The plaque samples were taken by means of sterile curettes from identical sites in all patients, viz, the buccal surfaces of the right maxillary first molar. The supragingival plaque samples obtained were then squeezed between two strips of filter paper to remove the saliva which, due to its alkaline pH, can give a false positive result. The dried plaque samples were then placed in a capped tube containing 1 ml of freshly prepared 10% w/v urea in deionized water (at pH 6.8) along with two drops of phenol red. The presence of urease activity results in an increase in pH to alkalinity, which is observed as a color change from yellow to pink. Although the oral flora contains many other bacterial species, such as a Streptococcus vestibularis and Actinomyces viscosus that are urease positive, such organisms usually cannot give positive results within an hour. 
Data was analyzed using SPSS, version 10, and was expressed as frequencies and percentages. We used the Chi-square (χ2 ) test and the Mann-Whitney U test to assess the significance of the differences between the groups. Multivariate logistic regression was performed to assess the risk posed by different factors (the odds ratios) for each group. To find out the common factors that influence the entire population, factor analysis was used, in which factor loadings based on eigenvalues were used to determine the factors. For all statistical evaluations, a two-tailed P < 0.05 was considered significant.
| Results|| |
The gender-wise age distribution was found to be not significant amongst the positive and negative controls (χ2 = 1.472; P > 0.05 and χ2 = 1.75; P > 0.05, respectively), whereas among the test cases it was significant (χ2 = 6.63; P < 0.05). The majority of the subjects were in the age-group of 30-49 years [Figure 1].
Religion as a cofounder was proved to be non-significant. Hindus constituted the majority of subjects in each group, which was a reflection of the distribution in the general population (χ2 = 0.824; P > 0.05) [Figure 2].
The distribution of regional differences of domicile, whether urban, periurban or rural, recorded any significant difference amongst the groups and was almost uniformly represented (χ2 = 7.260; P > 0.05). Most of the subjects in the study were residents of periurban areas [Figure 3].
Systemic disease status
The frequency of occurrence of systemic ailments like cardiovascular diseases and metabolic disorders were significantly different between the groups. The positive control cases had the highest prevalence of systemic afflictions, followed by the test cases. The negative controls did not have any of these ailments. Hypertension and diabetes were found to be the most common systemic ailments in all groups (χ2 = 22.913; P < 0.05) [Table 1].
Gastrointestinal disease status
Gastrointestinal disturbances like dyspepsia, chronic gastritis, gastroesophageal reflux, and PUD were found to be most prevalent in the positive control group, followed by the test cases. Negative controls did not report any such symptoms. Dyspepsia was the most common of the gastrointestinal symptoms. The differences were highly significant (χ2 = 17.661; P < 0.01) [Table 2].
Oral hygiene and periodontal disease status
The oral hygiene status was assessed and classified as 'good,' fair,' and 'poor' using the oral hygiene index of Greene and Vermillion.  The differences between the groups in the oral hygiene status were found to be highly significant (χ2 = 18.322; P < 0.01). The hygiene index was worst in the positive controls and poor in the test cases; the negative controls recorded fairly good oral hygiene status [Table 3].
The healthy volunteers had good periodontal status; the next best were the positive controls [Table 4]. The test cases showed the maximum prevalence of periodontal disease and the associated signs and symptoms. The differences between the groups were highly significant (χ2 = 19.584; P < 0.001). However, the majority of the patients recruited into this study were classified into the 'healthy' category as far as periodontal status was concerned.
The dental caries status in the different groups is depicted in [Table 5]. The positive controls registered the maximum caries load, followed by the test cases. The differences were highly significant (χ2 = 28.927; P < 0.001).
Rapid urease test
The RUT results were found to differ significantly between the groups [Table 6]. The test was positive in 52% of the positive controls and in 46% of the test cases, while it was positive in only 18% of the negative controls (χ2 = 13.887; P < 0.01).
Nonparametric comparisons using the Mann-Whitney U test showed highly significant differences between test cases and negative controls with respect to various parameters. RUT positivity showed significant (P < 0.01) difference between test cases and negative controls, and the ranks between them was found to be more than that of positive controls. Logistic regression analysis of RUT results and the different test variables showed the greatest risk factors for mucosal inflammation were gastrointestinal complaints and poor oral hygiene.
| Discussion|| |
The results of this study reveal that H. pylori is relatively common in the oral cavity, although the character of this oral colonization remains unclear as also the relationship of H. pylori with the persistent mucosal inflammation consistently noticed in OSF. Our results indicate that the presence of this organism in the oral cavity is incidental and that it has no specific role in mediating mucosal inflammation, given the high prevalence of this organism in non-OSF-associated oral mucositisl. Numerous conflicting studies have been published regarding the presence of H. pylori in the oral cavity. Some authors have shown that the prevalence of H. pylori colonization is relatively low, being seen in only about 38% of subjects,  while others have reported that it is present in nearly 90% or even 100% of subjects. , The major differences between these studies in study populations, sample collection methodologies, and sensitivity of the procedure used for detection of the bacteria make it difficult to compare the results of these studies. The major question is whether H. pylori is a commensal bacteria, comprising part of the biofilm of the oral cavity, or whether it plays a pathogenic role. Some investigators have suggested that H. pylori may contribute to the etiology of recurrent aphthous stomatitis.  Our study was limited to analyzing the presence of stomatitis and glossitis in association with OSF and the frequency of occurrence of H. pylori in this disorder compared with nonspecific inflammatory states of the oral mucosa in order to identify any causative role for the organism in the former. Though H. pylori is apparently capable of causing a nonspecific mucosal inflammatory state, we found no evidence linking H. pylori with OSF, which is in agreement with Okuda et al.  who concluded that H. pylori has only an incidental presence in oral cavity. This does not exclude the possibility that the bacteria contributes to the etiology of oral mucosal lesions such as stomatitis and glossitis. It appears that when the immunological status of the host is not compromised the presence of H. pylori in the oral cavity does not pose a risk for infection/reinfection of the oral mucosa or of any site in the gastrointestinal tract. However, when the oral environment changes, especially under the influence of disease states and/or habitual behavior (oral habits), bacterial colonization could take place and be the cause of mucosal inflammation. Mucosal inflammation, which is the common denominator associated with H. pylori colonization (irrespective of its association with OSF) could be considered a confounder complicating the morbid state of the disease and making oral functions difficult. The role of H. pylori in the causation of oral symptoms associated with OSF is therefore indirectly mediated, mainly through mucosal inflammation. The role played by the inflamed mucosa in aggravating the signs and symptoms of OSF cannot be overemphasized.
In the present case-control study, patients with nonspecific stomatitis and without clinical evidence of fibrosis constituted the positive controls and those without fibrosis and clinical evidence of inflammation formed the negative controls. Recruiting these two control populations was expected to give more specificity to the suspected association of this bacterium with the state of mucosal inflammation, consistently noticed in OSF. The confounders that we considered were sociodemographic variables, oral hygiene, sanitation, and standard of living. Univariate analysis showed that the three groups were similar in terms of the sociodemographic variables, indicating a minimal influence of these on the disease. There were no significant differences between the groups with regard to the distribution of place, systemic disease status (especially of gastrointestinal diseases), of residence (urban, periurban, or rural) and lifestyle/habits (smoking, chewing, and alcohol consumption) (χ2 = 7.260; P > 0.05).
With regard to the prevalence of systemic diseases, there were significant differences between the groups (χ2 = 22.913; P < 0.05). Systemic afflictions like hypertension, diabetes, cardiovascular diseases, and respiratory illness were most common among the positive controls, closely followed by test cases; the lowest prevalence was noted among the negative controls. Hypertension and diabetes were found to be the most common systemic illnesses in all groups.
There were significant differences between the groups in the prevalence of gastrointestinal diseases like dyspepsia, chronic gastritis, and gastroesophageal reflux (P < 0.01). These diseases were most prevalent in the positive controls, closely followed by the test cases. This result was expected and was in tune with the recorded frequency of occurrence of the organism H. pylori among the various groups. This was direct evidence in favor of the putative association of this bacterium with various gastrointestinal symptoms.  Dyspepsia was the commonest gastrointestinal problem noticed among the patients.
There were significant differences between the groups in the oral hygiene and periodontal disease status. These variables were worst among the positive controls, being somewhat better in the test cases. Oral hygiene status (assessed by the Greene and Vermillion index) was good among the negative controls (χ2 = 18.322; P < 0.01), as was the periodontal disease status (χ2 = 19.584; P < 0.001) which was estimated using the NHANES III protocol. The results of the present study show that there is a specific distribution pattern for H. pylori in the oral cavity, with a higher prevalence in plaque samples taken from the molars than from the premolars or incisors. This distribution may be in accordance with the microaerophilic characteristics of H. pylori. Theoretically, oxygen exposure decreases gradually from the incisors to the molars, favoring the growth of H. pylori in the molar region. Plaque composition varies from site to site and in response to various oral influences.  Therefore, it seems to be important to collect dental plaque samples from identical sites in the oral cavity.
The presence of H. pylori in dental plaque was examined by the RUT and the results were expressed as either positive or negative. Significant differences (P < 0.01) were noted between test cases and controls. RUT was positive in 52% of the positive controls, in 46% of the test cases, and in 18% of the negative controls. This result was also in accordance with the hypothesis that the positive control cases, who recorded poor oral hygiene, harbors more bacteria as part of the oral biofilm and are thus more prone to developing mucosal inflammation and the resulting clinical symptoms. The RUT has a sensitivity of 89-90% and specificity of 93-98% when done on gastric samples, as H. pylori is the only urease-positive bacterium known to reside in the stomach. The oral cavity, on the other hand, offers residence to several urease-producing bacteria, streptococcus sp., haemophilus sp., and actinomyces sp., and therefore it is inappropriate to conclude that high urease activity in dental plaque is indicative of the presence of it. But unlike H. pylori, these organisms will not give positive results within an hour and hence the significance of the RUT. This test is useful since it is simple and rapid and is therefore used routinely in clinicoepidemiological studies.
The results of this study were in agreement with the common wisdom that the high bacterial load noted in positive control cases as part of a poor oral hygiene status was directly responsible for the heightened mucosal inflammation seen in those cases. The test cases showed 46% RUT reactivity, only 6% short of that shown by the positive controls; in addition, the difference of 28% in the RUT reactivity between the test cases and the negative controls was statistically significant (χ2 = 13.887; P < 0.01). It is presumed that H. pylori, due to its proinflammatory properties, is partly responsible for the persistent inflammatory state seen in the test and control cases, which has got direct relevance in the modulation of the morbid clinical situation associated with OSF. A major clinical finding in this disease is the inability of the patient to open the mouth properly and this is partly ascribed to the persistent inflammatory state of the oral mucosa, especially of the buccal mucosa and the commissure. It has been reported by various investigators , that the inability to open the mouth is only partly due to the effect of submucosal fibrosis, other variables too playing a role in aggravating this handicap. The factors mainly incriminated are the state of the underlying musculature, the site of increased clinical involvement, and the involvement of pterygomandibular raphae; in addition, mucosal inflammation is also believed to contribute. In the present study, the RUT was employed to detect the presence of H. pylori in dental plaque. Studies have reported that the RUT has a specificity that is close to 100% and a sensitivity between 70% and 90%. , The sensitivity of RUT for determining H. pylori status in dental plaque is reported to be 89.7%, with a diagnostic accuracy of 86.7%.  It has been reported that other urease-positive microorganisms present in the oral cavity, such as Streptococcus vestibularis and Actinomyces viscosus, usually cannot give positive results within an hour.  The results obtained in the present study indicate that there was a high prevalence of H. pylori in dental plaque and that this may be associated with mucosal infection.
This possible association of H. pylori in dental plaque with the mucosal inflammatory state may have significant clinical implications. This is because the H. pylori eradication therapy commonly employed in the management of H. pylori-associated gastric disease has little impact on H. pylori residing within dental plaque.  Dental plaque, being a biofilm, offers a high degree of protection to the resident microflora from host defense mechanisms and systemically administered antibiotics. The role played by plaque bacteria in the recolonization of the gut and reinfection of the oral microenvironment after 'eradication' of H. pylori with systemic 'triple-drug regimen' is still a matter of conjecture. Once these relationships are better understood, intervention strategies, including mechanical and chemical plaque control measures, can be designed to better tackle H. pylori infection. This investigation, therefore, points to a hitherto unexplored aspect of the overall management of OSF, viz, the need for maintenance of a meticulous oral hygiene and scrupulous prophylactic measures as adjuvants in the treatment of this disease. This could be difficult to perform given the constraints enforced by restricted mouth opening and tongue protrusion of these patients but their role as part of the overall management of this crippling disorder cannot be overemphasized.
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King Saud University College of Dentistry, Riyadh
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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