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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 34  |  Issue : 3  |  Page : 143-150

Correlation of endodontic infection and cytokine expression in patients with systemic diseases: A systematic review of clinical studies


Department of Conservative Dentistry and Endodontics, Manav Rachna Dental College, Faridabad, Haryana, India

Date of Submission15-Jan-2022
Date of Decision16-Feb-2022
Date of Acceptance13-Apr-2022
Date of Web Publication30-Sep-2022

Correspondence Address:
Dr. Dax Abraham
PhD Scholar, Department of Conservative Dentistry and Endodontics, Manav Rachna Dental College, FDS, MRIIRS, Sec - 43, DelhiSurajkund Badkhal Road, Faridabad - 121 001, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/endo.endo_13_22

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  Abstract 


Aim: The role of various host response mediators in pulpitis has been extensively documented as these components may operate as biomarkers that reflect the condition of pulp tissues. The expression of these biomarkers is further affected in the presence of different systemic diseases. This review aims to assess if a correlation exists in the expression of cytokines and endodontic infection in patients having various systemic diseases undergoing nonsurgical endodontic therapy.
Materials and Methods: The review includes a complete manual search as well as electronic databases such as PubMed, Scopus, and EBSCOhost. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist was used to frame the review process. The critical appraisal checklist for quasi experimental studies developed by Joanna Briggs Institute was used to examine the risk of bias. For prospective clinical studies, eight criteria were used to assess the risk of bias. The studies included were clinical trials that estimated mRNA expression of cytokines from periapical interstitial fluid before and following disinfection of the root canals in patients suffering from various systemic diseases.
Results: This review included a total of four papers from the initial 122 publications. When compared to normal controls, endodontic infection was associated with altered expression of these cytokines in patients presenting various systemic diseases.
Conclusions: This information can subsequently be utilized to correctly distinguish between diseased and healthy pulp tissues. The interaction of cytokines in systemic diseases and their possible use in endodontics as a more precise and biologically based diagnostic tool can be planned.

Keywords: Cytokines, endodontic infection, systemic disorders


How to cite this article:
Abraham D, Singh A, Kurian AH, Gupta A, Aneja K, Sethi S. Correlation of endodontic infection and cytokine expression in patients with systemic diseases: A systematic review of clinical studies. Endodontology 2022;34:143-50

How to cite this URL:
Abraham D, Singh A, Kurian AH, Gupta A, Aneja K, Sethi S. Correlation of endodontic infection and cytokine expression in patients with systemic diseases: A systematic review of clinical studies. Endodontology [serial online] 2022 [cited 2022 Nov 30];34:143-50. Available from: https://www.endodontologyonweb.org/text.asp?2022/34/3/143/357696




  Introduction Top


Pulpitis is a frequent dental condition caused by the inflammation of the tooth pulp.[1] Caries, fractured restorations, unsuccessful vital pulp therapy, and trauma can all lead to pulpal inflammation. Root canal infections trigger a complicated immune response that includes cell recruitment along with the production of various inflammatory mediators.[2],[3],[4] Despite this fact, the immune response is ineffective in eliminating pathogens as the immune cells and molecules are unable to efficiently get into the dentin.[5] In the pulp tissue, a variety of cells which may fall in the category of immune or nonimmune such as dendritic cells, macrophages, odontoblasts, and endothelial cells are present that express toll-like receptors as innate immune receptors and can recognize pathogen-associated molecular pattern molecules and trigger immune responses.[6],[7]

Cytokines are nonantibody proteins that operate as intercellular mediators and are produced by inflammatory leukocytes and some nonleukocytic cells. They are not produced by specialized glands but rather by a range of tissue or cell types. They usually have a paracrine or autocrine effect rather than being endocrine (MeSH Unique ID: D016207). They are classified as either inflammatory or anti-inflammatory. Tumor necrosis factor-alpha (TNF-α), interleukin-8 (IL-8), IL-6, IL-2, and interferon-gamma are inflammatory cytokines, whereas IL-13, IL-10, and IL-4 are anti-inflammatory cytokines. The former facilitate as well as promote inflammation, whereas the latter, as the name suggests, decrease inflammation.[8]

Chemokines and their receptors, on the other hand, mediate the recruitment of leukocytes to diseased regions, such as the periradicular area.[9] The healing process is also aided by these mediators.[10]

Various studies have revealed a sturdy link between infections of the oral cavity and systemic illnesses, such as cardiovascular disease and diabetes mellitus.[11],[12],[13] Clinically, this association may be due to shared risk factors such insulin resistance and biological function dysregulation, including immune responses.[2] Other factors such as smoking, depression and stress, and human immunodeficiency virus infection have been identified to affect the immune response of the host, disrupting the equilibrium between lesion growth and tissue regeneration.[14]

The correlation between periapical or endodontic infections and systemic disorders such as chronic liver disease, malignant blood disorders requiring hematopoietic stem cell transplantation (HSCT), sickle cell anemia (SCA), and human immunodeficiency virus infection, as well as their shared pathological backgrounds in immunology as well as cytokine biology, is the focus of this systematic review. The aim of this review is to assess the presence of such a correlation which would aid in the use of such biomarkers as a potential tool to diagnose apical periodontitis.


  Materials and Methods Top


The systematic review technique was developed utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.[15]

Eligibility criteria

The PICO framework of systematic review was used to develop the review question, which defined the Population, Intervention, Comparison, and Outcome. The formulated PICO was “Is there a difference in the cytokine expression in patients with pulp necrosis or apical periodontitis having systemic diseases and undergoing endodontic therapy when compared to healthy subjects?”

Inclusion criteria

The publications with their titles and abstracts discovered during the electronic and manual searches were reviewed by two investigators (D. A. and A. S.). The articles that met the criteria for inclusion were weeded out. All of the remaining articles were retrieved and thoroughly screened by two of the above-mentioned reviewers to achieve a consensus. A criterion for the study inclusion was created, with papers published until August 2021 being included. Adult human patients who were being treated by nonsurgical endodontic therapy were the subjects of clinical investigations. Patients with pulp necrosis or apical periodontitis who had a systemic illness were included in the studies. The mRNA expression of cytokines in periapical interstitial fluid linked to infections of the root canal should be reported before and following the bacterial load in the studies assessed.

Exclusion criteria

Studies that evaluated the cytokine levels from samples other than periapical interstitial fluid were excluded. Patients who did not present systemic disorders were also excluded. All the studies in languages other than English were excluded as well.

Information sources and literature search strategy

An electronic search approach was employed in the Medline database of the US National Library of Medicine, which used a combination of keywords and indexing vocabulary (MeSH terms). The following terms and subject headings were used in our search: “cytokine,” “biological markers,” “inflammatory mediators,” “endodontic infections,” “pulpal diseases,” “pulpitis,” and “systemic diseases.”

Scopus and EBSCOhost employed the same electronic search approach as well as manual search of gray literature. Two examiners (D. A. and A. S.) independently conducted a systematic search for relevant research published up to August 2021. The search string in [Table 1] was created using the Boolean operators “AND” and “OR.” Duplicates were identified and excluded manually from the gathered data.
Table 1: Lists of keywords used in a search strategy for electronic databases

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Quality assessment and data extraction

Two authors (D. A. and A. S.) handsearched the pertinent articles from the whole database search. To determine accurate relevant data, the bibliography of review articles along with relevant papers was also reviewed. Finally, the information was organized into a PRISMA flowchart, as shown in [Figure 1]. Two examiners (D. A. and A. S.) extracted the data and analyzed each study by using the undermentioned parameters such as author year/country, language, journal, age group, gender, total patient size, case/study type, sample type, and type of cytokine estimated; risk of bias; and the evidence level determined according to the guidelines given by National Services Scotland.[16] Any disagreements between the two authors (D. A. and A. S.) were solved by the third author (A. K). The critical appraisal checklist for quasi-experimental studies developed by Joanna Briggs Institute was used to examine the risk of bias.[17] For prospective clinical studies, eight criteria were used to assess the risk of bias. The criteria assessing the follow-up were omitted as it is not possible in such studies. For all of the investigations, two evaluators (D. A., A. S.) independently applied the risk of bias, followed by a discussion of each issue. The third examiner (A. K.) resolved any disagreements to obtain a final consensus.
Figure 1: Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of the included ten studies in the systematic review

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  Results Top


The search approach yielded a total of 120 relevant articles, including both electronic and manual searches. Articles were screened for abstract evaluation after duplicates were eliminated, and 48 were chosen for full-text examination. After full-text analysis, only four publications were contained within the systematic review due to strict inclusion and exclusion criteria. The reasons for the exclusion of articles (n = 44) were as follows: (i) human dentition was not studied in any way; (ii) only a cell culture experiments were carried out; (iii) the studies that were off topic or investigation of a potential biomarker was not noted; (iv) no clear differentiation could be made between necrotic, irreversible, and reversible pulpitis; (v) studies where histologic traits or the presence of viruses, bacteria, or cells rather than biomarker quantification were emphasized; and (vi) editorials, comments, review articles, or case reports.

Study characteristics

Four studies[18],[19],[20],[21] were included in the final interpretation, all of which were related to mRNA expression of cytokines in periapical interstitial fluid linked to infections of the root canal before and after the bacterial burden was reduced by means of a cleaning process.

[Table 2] lists the specific characteristics of each of the studies examined.
Table 2: Characteristics of included studies

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Tissues studied

The clinical samples in all the four papers reviewed were obtained from periapical interstitial fluid nearby infections of the root canal, and groups were split based on clinical and radiographic examination, as well as pulp-sensibility tests. There were no symptoms of acute periapical periodontitis on the teeth while the consultation. Following isolation, disinfection, and access opening, paper points were positioned inside the root canal, maintained in place for 2 min, and later stored for microbiological investigation at 70°C. After the root canals had been cleansed and shaped, samples were taken again. For 1 min, the points were passively inserted 2 mm beyond the root apex. Points were nicked 4 mm from the tip, positioned in microcentrifuge tubes, and kept at 70°C.

Confirmatory tests

Reverse transcription-polymerase chain reaction (PCR) was the analytical procedure utilized to analyze the pulp tissue. On the basis of nucleotide sequences accessible in the GenBank database, primer sequences were generated using the PRIMER EXPRESS program. An ABI Prism 7900 HT Real-time PCR System was used to run the real-time PCR test. The PCR procedure contained a holding stage at 95°C for 10 min, a cycling stage of consisting 40 cycles at 95°C for 15 s and then 60°C for 1 min, and a melting curve stage consisting of 95°C for 15 s followed by 60°C for 1 min, and 95°C for 15 s. To test primer amplification, an Applied Biosystems SYBR-Green detection system was employed. To identify the precision of the amplified products, a melting curve analysis was done after amplification. To create the melting curve, continuous fluorescence quantities were recorded at each 1% rise in the temperature from 60° to 95°C. False positives were defined as PCR products with different melting temperatures than those calculated for reference DNA; a null fluorescence value was assigned to these cases. To normalize the data, the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was utilized with each set of assays. The samples were all ran twice. 1 mg cDNA was used in each reaction, which was carried out in a 25-mL container. Data were analyzed using Applied Biosystems' Sequence Detection System Software version 2.4.1 after amplification. The proportion of every unique primer to GAPDH expression was employed to define mRNA expression levels of all samples, and the levels of expression in all samples were computed as the mean value of the duplicates for every patient.

Cytokines studied

A total of ten cytokines were tested in the pulp tissue. At least one study found substantially significant differences among irreversible pulpitis and normal pulp for eight cytokines (80%). A statistically significant difference was not present among inflammation and health for two cytokines (CCL4 and CCL5).

Risk of bias

Out of the four studies, only one had a low risk of bias[18] while the other three had moderate risk.[19],[20],[21] Following the recommendations provided by National Services Scotland, the evidence level for each study was established.[16] All of the studies had an evidence level of 2+ except the study by Braga Diniz et al. (2021) which showed an evidence level of 2++ [Figure 2].
Figure 2: Risk of bias summary: review authors' judgments about each risk of bias item for each included study

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  Discussion Top


Apical periodontitis is the inflammation and destruction of periodontium which manifests as an apical radiolucent area.[22] Mobilization of inflammatory cells, secretion of cytokines, and synthesis along with activation of lytic enzymes are all involved in the initiation of this disease, resulting in periapical bone resorption.[23] The pro-inflammatory condition in addition to the damaged immune response linked to systemic disorders is able to alter the healing process of the pulpal tissue and periapical region.[24] According to Marending et al. (2005), the probity of the nonspecific immune system was a strong indicator of outcomes related to nonsurgical endodontic therapy and retreatment.[25] Ng et al. (2008) revealed the influence of a weakened nonspecific immune system on the repair of tissues in the periapical region.[26]

In a study conducted by Braga Diniz et al.,[18] it was noted that on day 7, the pre-HSCT group exhibited greater levels of TNF-α and interferon-gamma (IFN-γ) when equated to healthy/control group. This finding could be linked to neutropenia since it has long been related to HSCT patients.[27] Neutrophils have also exhibited a part in the initiation of bone loss linked to endodontic diseases.[28] Some studies have shown a marked increase in IFN-γ and TNF-α and expression after reduction of bacterial loads in healthy individuals.[19],[29] Prior research has found that root canal cleaning and shaping techniques result in a significant decrease in pro-inflammatory mediator expression.[20],[30],[31] The levels of IL-1β were considerably greater on day 7 than on the 1st day in the group before HSCT tested in this study, whereas in the control group, it was similar at both times. IL-1β has previously been shown to be elevated in periapical lesions[32],[33] and to be lowered after endodontic therapy.[20] CCL2 levels were similar in the control or healthy group immediately and 7 days following cleaning of the root canal, the same as established before.[34] CCL2/monocyte chemoattractant protein-1 (MCP-1) was undetected in the group before HSCT, implying that the employment of suitable effector cells to areas of inflammation was hampered in those individuals. As previously demonstrated,[35] the MCP-1/IL-10 ratio blends better when compared to IL-10 or MCP-1 alone, which may represent a disparity in the activity of anti-inflammatory and pro-inflammatory mediators in a particular disease. Furthermore, mice that lack MCP-1 demonstrate delayed re-epithelialization, wound healing, and lower capillary density in an experimental research.[36] CCL4 expression did not alter in the control group following the reduction of bacterial load in the root canal. It was also noted that there were no significant variations in CCL4 or CXCR4 expression between the two timeframes examined in the bone marrow group. Between days 0 and 7, there were no substantial variations in the levels of IL-10 in the control or healthy group, possibly because of cross-immune regulation generated by raised levels of pro-inflammatory cytokines including IFN-γ and TNF-α on day 7.

Braga Diniz et al. in their study[19] found that after cleaning and shaping processes, more significant expression of IFN-γ and TNF-α was identified among the controls or healthy group. Whereas, in patients with liver disease, higher expression levels of TNF-α were detected on the 7th day. Cleaning and shaping procedures, on the other hand, have demonstrated a reduction in the expression of pro-inflammatory mediators in previous studies.[20],[31] Furthermore, on day 7, IFN-γ and TNF-α levels in the controls were considerably greater in comparison with the patients having liver disease in this investigation. At the first collection, the patients with liver disease had greater IL-mRNA levels than the healthy or control group (day 0). These findings may be explained by the fact that the pattern and strength of cytokine expression vary significantly between individuals subject to the stimulatory agent used.[37],[38] Persons suffering from chronic liver disease have a greater as well as prolonged increase in circulating levels of TNF-α and IL-6 in response to sepsis than healthy patients.[39] Although there was absence of considerable difference in IL-6 production among the groups, significant measurable quantities of IL-6 were identified in the control as well as in patients with liver disease. In periapical tissues, IL-6 has been demonstrated to perform a protective effect. Therefore, IL-6-deficient mice show a significantly greater number of endodontic lesions than normal mice.[40] MCP-1/CCL2 expression was similar at different time frames for both the groups.

The results of a study by de Brito et al.[20] showed that expression levels of the pro-inflammatory mediators rose 7 days following root canal cleaning; although the immunoregulatory cytokines remained at baseline. The link between IL-17 and IFN-γ production has formerly been investigated in lesions of periapical origin,[41] and the findings are consistent with those shown here. Among HIV subjects, the expression levels of INF-y and IL1-b mRNA were considerably reduced, but IL-10 levels were raised after the bacterial burden was reduced. It has been observed that IL-10 has a substantial part in periapical and periodontal resorption of bone in animal models.[10] According to this study, the raised expression levels of Th1 cytokines, 7 days following cleaning of the root canal, appear to be liable for retaining decreased expression of the Th2-type mediator IL-10. The results also show that CCL2 and CCL4 expression was detectable in HIV+ people, but not CCL5; nonetheless, using primer amplification, it was found in periapical samples from in a positive control and among HIV subjects. Moreover, the findings of the investigation point toward the hypothesis that the anti-inflammatory actions of chemokines CCL2[42] and CXCR4[43] may cause a transition from a pro- to an anti-inflammatory response at a later time, as shown in HIV persons after reduction of bacterial load.

Ferreira et al.,[21] in their study, found that Th1-associated cytokines IFN-γ, IL-1β, IL-10, IL-17A, and TNF-α and chemokines CCL2/MCP-1 and CCL5 were substantially increased among SCA persons than in controls. Non-SCA persons, on the other hand, did not upregulate IL-1β, as established by various authors in primary infections[4],[31],[34] and in patients with refractory endodontic therapies.[44] Antibacterial activities of IL-1β may guard the persons against infection, but its powerful action on bone resorption, combined with substantially high levels of TNF-α, may impede the advancement and repair of periapical lesions in people suffering from SCA. IL-17A expression was also substantially higher than in control patients. These findings, like those of other periapical studies, show a favorable connection between IL-17 and IFN-γ.[6],[23] Despite the presence of CCL5 and CCL2/MCP-1 in samples attained from control, non-SCA, and SCA subjects, there was no substantial difference between the groups.

Limitations

Based on current understanding, this systematic review delivers an overview of cytokines that are at hand and quantifiable during the inflammation of the pulp in various systemic illnesses and hence could potentially serve as a diagnostic biomarker in cases of pulpal inflammation. Studies evaluating the cytokine expression in more prevalent systemic diseases such as diabetes mellitus and hypertension are needed. Moreover, additional clinical trials pertaining to the systemic diseases discussed above are required to draw a definitive correlation.


  Conclusions Top


When compared to noninflamed controls, irreversible pulpitis was related to altered expression of several cytokines in a variety of systemic diseases which could be utilized to tell the difference between damaged and healthy pulpal tissue. Identification, sampling and analysis of biomarkers or their subsets, that have been consistently associated with pulpal inflammation, are all current concerns in the therapeutic application of biomarkers. Given the paucity of data on the correlation between endodontic infections with systemic disorders, it is certain that further research is essential to entirely understand the presence of an association. A more exact diagnosis and vital pulp therapy regimen may result in improved clinical results if these challenges are addressed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

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