Review Article

Can Apical Periodontitis Modify Systemic Levels of Inammatory Markers? A Systematic Review and Meta-analysis
nke Gomes, DDS, MS,* Trevor Charles Blattner, DDS, Maximiliano Schu Manoel SantAna Filho, DDS, PhD,* Fabiana Soares Grecca, DDS, PhD,* Fernando Neves Hugo, DDS, PhD,* Ashraf F. Fouad, BDS, DDS, MS, and Mark A. Reynolds, DDS, PhD
Abstract
Introduction: This systematic review and metaanalysis investigated evidence to support whether apical periodontitis (AP) can modify the systemic levels of inammatory markers (IM) in humans. Methods: The MEDLINE, Embase, Cochrane, and PubMed databases were searched between 1948 and 2012, with no language restriction. Additionally, the bibliography of all relevant articles and textbooks were manually searched. Based on inclusion and exclusion criteria, 2 reviewers independently rated the quality of each study based on the Newcastle-Ottawa Scale. The primary outcome variable for meta-analysis was determined by the serum levels of IMs in AP subjects versus healthy controls or in AP subjects before versus after treatment intervention. Results: Among the 531 initially identied articles, 20 comprised the nal analysis. Thirty-one different IMs were analyzed, with immunoglobulin (Ig) A, IgM, IgG, and C-reactive protein (CRP) being the most commonly investigated. CRP, interleukin (IL)-1, IL-2, IL-6, asymmetrical dimethylarginine, IgA, IgG, and IgM were shown to be increased in patients with AP compared with controls in most studies. Metaanalyses showed that serum levels of IgA (P = .001), IgG (P = .04), and IgM (P < .00001) were increased in humans with AP compared with healthy controls and serum levels of CRP, IgA, IgE, IgG, and IgM were not signicantly different between patients with AP before and after treatment (P > .05). Conclusions: Available evidence is limited but consistent, suggesting that AP is associated with increased levels of CRP, IL-1, IL-2, IL-6, asymmetrical dimethylarginine, IgA, IgG, and IgM in humans. These ndings suggest that AP may contribute to a systemic immune response not conned to the localized lesion, potentially leading to increased systemic inammation. (J Endod 2013;39:12051217)

Key Words
Apical periodontitis, inammation, meta-analysis, vascular diseases

nammation plays an important role in the pathogenesis of atherosclerosis and in its systemic complications (1). Studies have shown that serum levels of inammatory markers (IMs) are predictors of cardiovascular disease risk (2, 3). These markers include cell adhesion molecules, cytokines (including interleukins [ILs] and tumor necrosis factors [TNFs]), proatherogenic enzymes, immunoglobulins (Igs), transforming growth factors, and acute phase proteins such as serum amyloid A and C-reactive protein (CRP). Baseline levels of cell adhesion molecules (46), CRP (713), TNF (14, 15), or IL-6 (16, 17) were found to be associated with a risk of future myocardial infarction, stroke, peripheral vascular disease, and cardiovascular death among apparently healthy populations. High concentrations of CRP, serum amyloid A, and IL-6 were also correlated with the risk of insulin resistance and metabolic syndrome (18, 19). In addition, CRP and IL-6 or IL-8 were associated with adverse respiratory outcomes, such as diminished lung function (20) and chronic obstructive pulmonary disease (21). Furthermore, late-onset Alzheimer disease and cerebrovascular dementia were related to higher circulating levels of IL-6, IL-1 beta, and TNF alpha (22). During the last 2 decades, a connection between chronic low-grade oral infection and inammation and the slow progression of unfavorable systemic vascular effects has emerged (7, 2326). Periodontal disease and periapical lesions are prevalent longterm infectious diseases that cause chronic inammatory reactions. A number of studies have shown bacteria of oral origin in atherothrombotic plaques or vascular biopsies (2735). Detailed reviews exploring the potential pathogenic mechanisms linking oral infections and atherosclerosis can be found in the literature (24, 36, 37). Most of the evidence linking oral diseases to increased serum levels of IMs comes from studies on chronic periodontal disease. It has been suggested that systemic dissemination of IL-6 and CRP as a consequence of periodontal disease can lead to

From the *School of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Medical and Dental Center of the Military Police of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Departments of Endodontics, Prosthodontics and Operative Dentistry, and Periodontics, School of Dentistry, University of Maryland, Baltimore, Maryland. Supported in part by the CAPES Foundation, Ministry of Education of Brazil (doctorate scholarship number 1433/11-3) and in part by the Military Police, State Government of Rio Grande do Sul, Brazil. Address requests for reprints to Dr Maximiliano Sch unke Gomes, Postgraduate Program, School of Dentistry, Federal University of Rio Grande do Sul, R Ramiro Barcelos, 2492/503, 90035-003 Porto Alegre, RS, Brazil. E-mail address: endomax@gmail.com 0099-2399/$ - see front matter Copyright 2013 American Association of Endodontists. http://dx.doi.org/10.1016/j.joen.2013.06.014

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adverse vascular effects on endothelium and cardiac smooth muscles (38, 39). Other studies indicate that PGE-2 and TNF alpha from inamed periodontal tissues in pregnant women can reach the placenta and amniotic liquid, contributing to preterm birth (4042), even though the treatment of periodontitis in pregnant women does not signicantly alter rates of preterm birth, low birth weight, or fetal growth restriction (43). Increased plasma levels of TNF alpha, IL-6, and CRP are highly related to insulin resistance, hindering the entry of glucose into the cells (44, 45). Moreover, gingivitis was associated with an increased serum level of IL-6 among nonsmoking diabetic patients in the Atherosclerosis Risk in Communities Study (46). The biological pathways thought to underlie the link between chronic periodontal disease and systemic disorders are the same as those potentially linking chronic apical periodontitis (AP) and general health. In many aspects, microbiological characteristics of periodontal disease are similar to infections of endodontic origin (47, 48). Both types of infection are associated with complex microora, with predominantly anaerobic gram-negative rods being the most common bacterial type. Likewise, inammatory responses that accompany periodontal disease and AP are similar (49). In patients with such lesions, areas of considerable bone resorption act as a reservoir of IMs and antibodies, including TNF alpha, IL-1 beta, PGE-2, IL-1 beta, IL-8, IgA, and IgG (50). The anatomic proximity of endodontic and periodontal infections with the bloodstream can result in bacteremia during treatment (51) or daily activities (52). Moreover, in contrast to periodontal infections, no epithelial barrier is found between the necrotic infected root canal and the highly vascular granulomatous tissue in periapical infections. Systemic spread of bacterial products may occur as well as the dissemination of inammatory mediators and immune complexes (49, 53), with possible induction and/or perpetuation of systemic adverse effects. Recent epidemiologic investigations have proposed an association between chronic AP (54) or a history of endodontic treatment (55, 56) and adverse cardiovascular outcomes. Nevertheless, contrary to the evidence regarding periodontal disease, it is unclear whether individuals with AP, in fact, present variations in the serum levels of IMs. Therefore, the purpose of this study was to systematically review the literature for evidence on the association between AP and systemic levels of IMs in humans. The clinical question to be answered may be framed as follows: when compared with individuals with healthy periapical status, are the systemic levels of IMs altered in patients with AP? Duplicate studies were identied and discarded. The remaining articles were subjected to stricter inclusion and exclusion criteria.

Study Selection and Inclusion and Exclusion Criteria The full texts of the remaining articles were obtained and reviewed independently by 2 reviewers (M.S.G. and T.C.B.) based on the following inclusion criteria:
1. The type of study: clinical trials or case-control studies or crosssectional studies or cohort studies 2. Studies assessing symptomatic or asymptomatic AP 3. Studies in which systemic IMs were quantied and the periapical condition was established Exclusion criteria included the following: 1. The type of study: cell culture laboratory studies or animal studies 2. Studies that evaluated local IMs only including gingival crevicular uid samples and/or samples from periapical lesions Cases of disagreement between reviewers were discussed until a consensus was reached.

Quality Assessment and Data Extraction Potentially relevant studies were subjected to a comprehensive text evaluation, including data extraction, methodologic quality analysis, and data synthesis and analysis. The parameters recorded for each study were the following: authors names, date of publication, study purpose, sample size, subject homogeneity, periapical diagnoses, study design, and ndings. Reviewers independently rated the quality of each study based on established criteria and the Newcastle-Ottawa Scale (NOS) (61), and a consensus was reached. After reviewing and rating the studies, statistically signicant changes in the levels of IMs in patients with periapical disease were coded as either present or absent for each study. Outcome Variables and Statistical Analysis The primary outcome variable was determined by the serum levels of different IMs (mean and standard deviation) in AP subjects versus the healthy control group (for cross-sectional, case-control, and interventional studies) or AP subjects before treatment versus AP subjects after treatment (for interventional studies exclusively). Given the heterogeneity among IMs evaluated in different studies, data were primarily analyzed from a descriptive point of view. Those studies with a similar design and evaluating the same IM were grouped, and a subgroup meta-analysis was performed evaluating the most prevalent markers using RevMan 5.1 (The Nordic Cochrane Center, Copenhagen, Denmark, 2011). When heterogeneity was present (I2 $ 50%), a random effects model was used to summarize the data. If heterogeneity was not present (I2 < 50%), a xed effect model was used. The value for rejection of the null hypothesis was set at P # .05.

Methods
Literature Search Strategy A search was undertaken to identify all the studies that reported on the relationship between AP and circulating or systemic levels of IMs. The MEDLINE (Ovid), Embase, PubMed, and Cochrane Library databases were searched for human studies published between 1948 and 2012 (last accessed September 13th, 2012) using the following key words: (periapical diseases/exp OR lesions of endodontic origin OR periapical tissue/exp OR periapical lesions OR apical lesions OR periradicular lesions) AND (blood/exp OR blood OR serum/exp OR serum) AND (cytokines/exp OR cytokines OR immunoproteins/ exp OR immunoproteins OR endopeptidases OR advanced glycosylation end products OR prostagandin-endoperoxidase synthases OR acute phase proteins/exp OR acute phase proteins OR c-reactive protein/exp OR c-reactive protein OR serum amyloid a). Additionally, the bibliographies of all relevant articles as well as the bibliographies of the pertinent chapters in relevant textbooks (5760) were manually searched. No language restriction was applied to the search. Titles and abstracts of the studies selected in this preliminary analysis were then scanned, and the relevance of each study was determined.
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Results
Results from the electronic search yielded a total of 531 hits. After duplicate references were discarded, a subsequent search at the title and abstract level revealed 30 articles for full-text reading, 9 of which were identied through a hand search (6271). At this level, 10 studies were excluded, and reasons for exclusions are listed in Table 1.

Study Characteristics Twenty studies were included in the nal analysis. Their main characteristics and ndings are presented in Table 2. The 20 included studies can be divided into 2 main groups: (1) interventional studies
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TABLE 1. Excluded Studies and Reasons for the Exclusions Study
Janicha (1981) (62) Marton et al (1987) (105) Takahashi et al (1997) (69) Euler et al (1998) (106) Matsushita et al (1999) (107) De Soet et al (2003) (70) Kosugi et al (2003) (96) Meurman et al (2003) (108) Arrol et al (2010) (109) Motta et al (2010) (110)

Reason for exclusion

Merged with other study (90) because of similarity of study design and subjects. Merged with other study (85) because of similarity of study design and subjects. Periradicular tissue samples were evaluated instead of serum levels of IMs. Cytokine production by neutrophils from periradicular tissue samples were evaluated instead of serum levels of IM. The study evaluated the induction of cytokines by lipopolysaccharides from species of endodontopathic black-pigmented bacteria instead of serum levels of IMs. The study determined whether dental caries where associated with induction of the systemic immune system or cytokine response, but no specic data regarding AP patients and its serum levels of IM is available. All subjects were patients with pustulosis palmaris et plantaris, a condition that may inuence the serum levels of IMs. Levels of IMs available only for the comparison between CHD patients and non-CHD patients but not for a comparison between AP subjects and non-AP subjects. The study was based on a postal self-report questionnaire to evaluate history of endodontic treatment; no clinical or radiographic examinations were performed. All subjects were leprosy patients, a condition that may inuence the serum levels of IMs.

(n = 9) assessing systemic IM levels before and after the intervention (ranging from tooth extraction to nonsurgical root canal treatment, surgical root canal treatment, prescription of antibiotics, or drainage) and (2) cross-sectional (n = 8) or case-control (n = 3) studies assessing systemic IM levels in patients with AP compared with control patients without AP. The quality ratings of each study as evaluated according to NOS criteria are presented in Tables 3 and 4. Overall, 16 of the 20 studies showed statistically signicant differences in levels of selected systemic IMs in subjects with AP compared with controls, namely, subjects without AP or subjects with AP after effective treatment. Four studies revealed no signicant difference between patients with AP and controls. Three studies included exclusively asymptomatic AP, 7 studies included only symptomatic AP, 8 studies included both symptomatic and asymptomatic AP, and 2 studies did not report on the type of AP. Thirty-one different IMs were evaluated in the included studies, with the most common markers being IgG (n = 8), CRP (n = 6), IgM (n = 6), and IgA (n = 5). Table 5 shows the list of IMs evaluated in all included studies, the type of AP (symptomatic, asymptomatic, or both) considered in each study, and whether the difference to control groups was signicant.

(Fig. 2A), and heterogeneity was present (I2 = 86%). Of the 3 interventional studies evaluating IgA, results from 2 studies including 86 patients were available for meta-analysis (Fig. 2B). Results from 2 interventional studies evaluating IgE including 28 patients were available for metaanalysis (Fig. 2C), and of 4 interventional studies evaluating IgG, results from 3 studies including 81 patients were available for meta-analysis (Fig. 2D). Of 4 interventional studies evaluating IgM, results from 3 studies including 81 patients were available for meta-analysis (Fig. 2E). No signicant differences were found in the systemic levels of CRP (P = .22), IgA (P = .53), IgE (P = .31), IgG (P = .75), and IgM (P = .76) in patients with AP before treatment compared with patients with AP after the intervention.

Discussion
Systemic inammation appears to play an important role in the development of many debilitating diseases including cardiovascular disease among others (2, 3). To our knowledge, the present study is novel in summarizing the available evidence to respond whether patients with AP present modications in serum levels of IMs. Although the limitations related to available studies, ndings from this systematic review reveal a generalized increase in systemic IMs in humans with AP compared with controls. The question of whether and to what extent the inammation secondary to AP may impair general health is important because it may fundamentally inuence the therapeutic strategy. Moreover, the present results reinforce the biological plausibility of an association between AP (54), pulpal inammation (55) or a history of endodontic treatment (56, 72), and adverse cardiovascular outcomes. Several epidemiologic investigations have suggested associations between poor oral health and adverse systemic outcomes, including mortality (73), cardiovascular diseases (54, 7478), atherosclerosis (79), respiratory diseases (80, 81), and other systemic conditions (46, 8284). In order for these associations to be validated in future studies and in order for adequate interventional studies to be designed, the present study summarizes the evidence relating systemic markers of inammation to endodontic infection. The evidence supports the hypothesis that IMs of periapical disease can be used to assess the systemic response to endodontic infection and treatment. The present results need to be interpreted with some caution. The studies included in this systematic review represent the best available evidence, but numerous limitations related to heterogeneity, study designs, controls, sample sizes, and other methodologic aspects must be appropriately discussed. There was a remarkable variability among 1207

Meta-analysis of IMs: AP Subjects versus Healthy Controls Of the 5 studies evaluating IgA, results from 2 studies including 96 patients were available for meta-analysis (Fig. 1A). Systemic IgA levels were signicantly higher in patients with AP compared with healthy controls (P = .001). Of the 4 studies evaluating IgE, results from 3 studies including 84 patients were available for meta-analysis (Fig. 1B). Heterogeneity was present (I2 = 73%), and systemic IgE levels were not different in patients with AP compared with healthy controls (P = .10). Of the 8 studies evaluating IgG, results from 5 studies including 310 patients were available for meta-analysis (Fig. 1C). Heterogeneity was present (I2 = 68%), and systemic IgG levels were signicantly higher in patients with AP compared with healthy controls (P = .04). Of the 6 studies evaluating IgM, results from 3 studies including 105 patients were available for metaanalysis (Fig. 1D). Systemic IgM levels were signicantly higher in patients with AP compared with healthy controls (P < .00001). Meta-Analysis of IMs: AP Subjects before and after Intervention Of the 4 interventional studies evaluating CRP, results from 2 studies including 75 patients were available for meta-analysis
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TABLE 2. Characteristics, Main Results, and Limitations of the Studies Included in the Systematic Review (N = 20)
Study Inammatory markers (outcome) CRP Study design CS AP (exposure) A/S Population (N*/n) Adults (23/19) Mean age (*/) NR/NR Follow-up period 8 days Type of intervention Antibiotics and TE Main results Among 23 subjects with AP, 13 (56.5%) presented increased CRP. Signicant difference compared with healthy and gingivitis-only subjects. Increases in serum levels of gamma-globulin fractions were directly related to degree of changes in periapical tissues (AP). Signicant decrease in alpha-2 and gamma-globulin levels after treatment. Subjects with AP showed a signicantly greater degree of inhibition of LIF than controls. Signicant differences after treatment in lymphocytes and monocytes count, ESR, albumin, total proteins, alpha-2 globulin and IgG. Signicant increase in serum levels of IgE in AP subjects at baseline. No difference in serum levels of IgG, IgM, IgA, and IgD between AP subjects and controls at baseline. No differences after intervention. No statistical difference in serum levels of CIC, IgG, IgM, and C3 between subjects with AP and controls. Signicant increase on CIC, IgG, IgM in AP compared to healthy subjects. 26.9% increase in IgG levels in AP subjects. Signicant decrease after AP treatment for all markers. Signicant difference between mean IgE levels of AP subjects and controls. Observations and limitations Sample size and drop-off rate (80.0%) at followup. Method to measure CRP. Control for systemic confounders not reported. No statistical analysis. Periodontal disease measures not reported. All subjects had rheumatism, which is an important confounder.

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Boucher et al (1967) (104)

Matlashenko (1968) (95)

Alpha-2 and gammaglobulin fractions

Adults (47/58)

1445 years old

2 months; 1 Year

Unspecied surgical intervention and rehabilitation of the oral cavity

Stabholz and McArthur (1978) (111)

Release of LIF by lymphocytes

CS

A/S

Adults (9/5)

2030 years old

Sample size. In vitro stimulation of leukocytes from blood. Sample size. Periodontal status not reported.

Janicha (1983) (90)

White blood cell count, ESR, protein fractions, IgA, IgC, IgM, IgG

A/S

Children (34/10)

611 years old

21 days

TE

Svetcov et al (1983) (63)

IgG, IgM, IgA, IgE, IgD

Adults (9/4)

2063 years old

10 to 14 days

Antibiotics prescription

Limited sample size. Intervention was only the prescription of antibiotics, but not the endodontic treatment or extraction.

Torabinejad et al (1983) (112)

CIC, IgG, IgM, C3

CS

Adults (30/30)

35.0/38.6

Controlled for periodontal disease and systemic disorders.

Kettering and Torabinejad (1984) (64)

CIC, C3, IgE, IgG, IgM

Adults (35/30)

31.6/38.6

NR

NSRCT or TE

Nevins et al (1985) (65)

IgE

CS

Adults (20/20)

14 to 62 years old

Sample size. 13 (37%) out of 35 subjects with AP had increased CIC and were recalled; only 8 out of 13 were submitted to a second blood sample (drop-off rate of 38.5% at follow-up). Controlled for periodontal disease and systemic disorders. (Continued )

TABLE 2. (Continued )
Study Marton et al (1988) (66) Inammatory markers (outcome) AAT, AMG, CRP, HPT, C3, CER Study design I AP (exposure) A/S Population (N*/n) Adults (36/) Mean age (*/) 26.3/ Follow-up period 7 days; 3 months Type of intervention SRCT Main results All except HPT were slightly increased at baseline. Signicant decrease within 7 days for AAT and CER. Signicant decrease in 3 months for all, including CRP (40.7% decrease). Signicant increase on IgM, AAT, CRP, and NRC at baseline. Signicant decrease in all acutephase proteins and NRC after 3 months of treatment, including a 40.9% reduction on CRP levels. CRP not altered after 7 days. IgG not signicantly changed. CTA signicantly increased after treatment. Signicant difference on Prevottella Intermedia reactive IgG levels in serum from AP subjects compared to healthy controls. Signicant increase on CIC (78.8 %) in AP subjects compared to controls. No statistical difference in serum levels of IgG, IgM and IgA between subjects with AP and control. Signicant increase in serum levels of IgE in AP subjects. Serum concentrations of IL1a, IL-1b, IL-2, IL-6, IL-8, ITF-g, G-CSF were undetectable in subjects with AP. Only one subject (6.25%) presented high levels of TNF-a and GMCSF. Signicant increase on H2O2 and O2 production by unstimulated PMNs in AP subjects versus controls at baseline. Signicant decrease on H2O2 and O2 production by unstimulated PMNs after treatment. Observations and limitations Sample size and mean dropoff rates (21.2% at 7 days) and (54.5% at 3 months).

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Marton and Kiss (1992) (85)

IgA, IgG, IgM, AAT, AMG, CRP,C3, CER, HPT, CTA, lymphocytes, NRC

A/S

Adults (36/)

26.3/

7 days; 3 months

SRCT

Sample size. Drop-off rates not reported. Same population of a previous study (66).

Baumgartner et al (1992) (71)

IgG

CS

NR

NR (11/17)

NR

Age and denition of AP not reported. Controlled for periodontal disease.

Anil et al (1993) (113)

CIC

CC

Adults (45/40)

24.5/24.0

Sample size. CIC are not specied. Limited sample size. Very limited sample (N=3) for IgE.

SantAna Filho et al (1994) (68)

IgG, IgM, IgA, IgE

CS

Adults (8/)

2566 years old

Matsushita et al (1998) (114)

IL-1a, IL-1b, IL-2, IL-6, IL-8, TNF-a, ITF-g, G-CSF, GMCSF

CS

Adults (10/6)

NR/NR

Sample size. Limited data on serum levels of IM. Study focused on in vitro bacterial stimulation of cytokines.

Minczykowski et al (2001) (67)

H2O2 and O2 production by stimulated and unstimulated PMNs

A/S

Adults (20/20)

33.8 age matched

14 days

TE

Sample size. PMNs were stimulated in vitro.

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(Continued )

TABLE 2. (Continued )
Study Inammatory markers (outcome) IgA, IgG Study design CS AP (exposure) A/S Population (N*/n) Children (44/57) Mean age (*/) 10.7/9.9 Follow-up period Type of intervention Main results Signicant increase on IgA (30.2%) and IgG (9.5%) in AP compared to healthy subjects. 60% of subjects with AP presented increased CRP at baseline, which is signicant compared to healthy subjects. Signicant decrease in CRP levels (78.8% decrease) after AP treatment. Signicant association between AP subjects and high levels of CRP (OR = 2.2, CI = 1.3-3.7) and neopterin (OR = 2.7, CI = 1.4-5.2) at baseline. Nonsignicant weak correlation between CRP and AP. No relationship between AP and number of leucocytes. Observations and limitations Sample size.

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Cogulu et al (2007) (91)

Ren and Malmstrom (2007) (86)

CRP

Adults (14/10)

34.3/NR

7 days

TE or drainage (emergency treatment)

Sample size and drop-off rate (28.6%) in AP group at follow-up. Subjects in groups other than AP were obese (BMI >33), which is a confounder.

De Soet et al (2008) (92)

CRP, AGP, neopterin

A/S

Children (120/53)

6.0/6.0

1 year

TE

Willershausen et al (2009) (88)

CRP, leucocytes

CC

Adults (138/102 -total) (77/43 - AMI subjects)

61.8(AMI)/63.4 (non-AMI)

Cotti et al (2011) (93)

IL-1, IL-2, IL-6, TNF-a, ADMA

CC

NR

Adults (20/20)

35.3/27.0

Signicant increase in serum levels of IL-1, IL-2, IL-6 and ADMA in AP subjects. No difference in TNF-a levels.

Intervention was not specic for AP, including full dental treatment (periodontal, ATR, etc.). Periodontal disease is a confounder. Sample consists predominantly of males. CRP levels are shown only between AMI group, which is an important confounder. Additionally, periodontal disease is a confounder. Sample size. Include only males. Good method: controlled for periodontal disease, tooth loss and CV risk factors.

A, asymptomatic apical periodontitis; AAT, alpha-1-antitrypsin; ADMA, asymmetrical dimethylarginine; AGP, alpha-1-acid glycoprotein; AMG, alpha-2-macroglobulin; AMI, acute miocardial infarction; AP, apical periodontitis; ATR, atraumatic restorative treatment; BMI, body mass index; C3, complement C3 component; CC, case-control study; CER, oxidase activity of ceruloplasmin; CIC, circulating immune complexes; CRP, C-reactive protein; CS, cross-sectional study; CTA, complement activity; ESR, erythrocyte sedimentation rate; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte macrophage-colony stimulating factor; HPT, haptoglobin; I, interventional study; Ig, immunoglobulin; IL, interleukin; IM, inammatory marker; ITF, interferon; LIF, leukocyte migration inhibition factor; NR, not reported; NRC, neutrophil leukocyte-related chemiluminescence; NSRCT, nonsurgical root canal treatment; PMNs, polymorphonuclear neutrophils; S, symptomatic apical periodontitis; SRCT, surgical root canal treatment; TE, tooth extraction; TNF, tumor necrosis factor. *Subjects with apical periodontitis. Subjects in the control group without apical periodontitis. This study followed up only 2 subjects in the symptomatic AP group; thus, it was considered a cross-sectional study. Reference values were used for comparability at baseline.

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TABLE 3. Methodologic Quality Assessment of Cohort and Interventional Studies According to NOS Criteria (N = 9) Matlashenko Janicha Svetcov et al (1968) (95) (1983) (90) (1983) (63)
* * * * * * * *

NOS criteria
Selection 1 Representativeness of the exposed cohort 2 Selection of the non-exposed cohort 3 Ascertainment of exposure 4 Demonstration that outcome of interest was not present at start of study Comparability 1 Comparability of cohorts on the basis of the design or analysis Outcome 1 Assessment of outcome 2 Was follow-up long enough for outcomes to occur 3 Adequacy of follow-up of cohorts (<20%) Total awarded stars

Kettering and Marton and Torabinejad Marton et al Kiss (1992) Minczykowski Ren and Malmstrom De Soet et al (1984) (64) (1988) (66) (85) et al (2001) (67) (2007) (86) (2008) (92)
* * * * * * * * * * * * *

* * * * 7

* * * * 7

* * * * 6

* * 4

* * * 4

* * * 4

* * * * 6

* * * 6

* * * * 8

A study can be awarded a maximum of 1 star for each numbered item within the selection and exposure categories. A maximum of 2 stars can be given for comparability.

TABLE 4. Methodologic Quality Assessment of Case-control and Cross-sectional Studies According to NOS Criteria (N = 11) Boucher, Hanrahan, Kihara (1967) (104)
* * *

NOS criteria
Selection 1 Is the case denition adequate 2 Representativeness of the cases 3 Selection of controls 4 Denition of controls Comparability 1 Comparability of cases and controls on the basis of the design or analysis Exposure 1 Ascertainment of exposure 2 Same method of ascertainment for cases and controls 3 Nonresponse rate Total awarded stars

Stabholz, McArthur (1978) (111)

* * *

Torabinejad et al (1983) (112)

* * **

Nevins et al (1985) (65)

* * * **

Baumgartner et al (1992) (71)

* *

Anil et al (1993) (113)

* * **

SantAna Filho et al (1994) (68)

* *

Matsushita et al (1998) (114)

* * **

Cogulu et al (2007) (91)

* * **

Willershausen et al (2009) (88)

* *

Cotti et al (2011) (93)

* * * **

Review Article

* * NA 5

* * NA 5

* * NA 6

* * NA 7

* * NA 4

* * NA 6

* * NA 4

* * NA 6

* * NA 6

* * NA 4

* * NA 7

NA, does not apply. A study can be awarded a maximum of 1 star for each numbered item within the selection and exposure categories. A maximum of 2 stars can be given for comparability.

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TABLE 5. List of Inammatory Markers Evaluated in All Included Studies, Type of AP, and Whether the Difference to the Control Was Signicant
Inammatory marker IgA Study Janicha (1983) (90) Svetcov et al (1983) (63) Marton and Kiss (1992) (85) SantAna Filho et al (1994) (68) Cogulu et al (2007) (91) Janicha (1983) (90) Svetcov et al (1983) (63) Svetcov et al (1983) (63) Kettering and Torabinejad (1984) (64) Nevins et al (1985) (65) SantAna Filho et al (1994) (68) Janicha (1983) (90) Svetcov et al (1983) (63) Torabinejad et al (1983) (112) Kettering and Torabinejad (1984) (64) Marton and Kiss (1992) (85) Baumgartner et al (1992) (71) SantAna Filho et al (1994) (68) Cogulu et al (2007) (91) Janicha (1983) (90) Svetcov et al (1983) (63) Torabinejad et al (1983) (112) Kettering and Torabinejad (1984) (64) Marton and Kiss (1992) (85) SantAna Filho et al (1994) (68) Boucher et al (1967) (104) Marton et al (1988) (66) Marton and Kiss (1992) (85) Ren and Malmstrom (2007) (86) De Soet et al (2008) (92) Willershausen et al (2009) (88) Torabinejad et al (1983) (112) Kettering and Torabinejad (1984) (64) Anil et al (1993) (113) Torabinejad et al (1983) (112) Kettering and Torabinejad (1984) (64) Marton et al (1988) (66) Marton and Kiss (1992) (85) Matsushita et al (1998) (114) Cotti et al (2011) (93) Matsushita et al (1998) (114) Cotti et al (2011) (93) Matsushita et al (1998) (114) Cotti et al (2011) (93) Matsushita et al (1998) (114) Matsushita et al (1998) (114) Cotti et al (2011) (93) Matsushita et al (1998) (114) Matsushita et al (1998) (114) Matsushita et al (1998) (114) Janicha (1983) (90) Marton and Kiss (1992) (85) Willershausen et al (2009) (88) Stabholz and McArthur (1978) (111) Minczykowski et al (2001) (67) Matlashenko (1968) (95) Janicha (1983) (90) De Soet et al (2008) (92) De Soet et al (2008) (92) Cotti et al (2011) (93) Marton et al (1988) (66) Marton and Kiss (1992) (85) Marton et al (1988) (66) Marton and Kiss (1992) (85) Janicha (1983) (90) Marton et al (1988) (66) Marton and Kiss (1992) (85) Marton et al (1988) (66) Marton and Kiss (1992) (85) Marton and Kiss (1992) (85) Marton and Kiss (1992) (85) Type of AP A/S S A/S A A/S A/S S S S A A A/S S A S A/S NR A A/S A/S S A S A/S A A/S A/S A/S S A/S A A S A A S A/S A/S A NR A NR A NR A A NR A A A A/S A/S A A/S A/S A A/S A/S A/S NR A/S A/S A/S A/S A/S A/S A/S A/S A/S A/S A/S Difference to control Nonsignicant Nonsignicant Nonsignicant Nonsignicant Signicant Nonsignicant Nonsignicant Signicant Signicant Signicant Signicant Signicant Nonsignicant Nonsignicant Signicant Nonsignicant Signicant Nonsignicant Signicant Nonsignicant Nonsignicant Nonsignicant Signicant Signicant Nonsignicant Signicant Signicant Signicant Signicant Signicant Nonsignicant Nonsignicant Signicant Signicant Nonsignicant Signicant Signicant Signicant Nonsignicant Signicant Nonsignicant Signicant Nonsignicant Signicant Nonsignicant Nonsignicant Nonsignicant Nonsignicant Nonsignicant Nonsignicant Signicant Signicant Nonsignicant Signicant Signicant Signicant Signicant Signicant Nonsignicant Signicant Signicant Signicant Signicant Signicant Signicant Nonsignicant Nonsignicant Signicant Signicant Signicant Signicant

IgC IgD IgE

IgG

IgM

CRP

CIC C3

IL-1 IL-2 IL-6 IL-8 TNF alpha ITF gamma G-CSF GM-CSF Leucocytes/white blood cell count Release of LIF by lymphocytes H2O2 and O2 production by stimulated and unstimulated PMNs Alpha-2, Gamma-globulin and other protein fractions Neopterin AGP ADMA AAT AMG ESR HPT CER CTA NRC

A, asymptomatic apical periodontitis; AAT, alpha-1-antitrypsin; ADMA, asymmetrical dimethylarginine; AGP, alpha-1-acid glycoprotein; AMG, alpha-2-macroglobulin; AP, apical periodontitis; C3, complement C3 component; CER, oxidase activity of ceruloplasmin; CIC, circulating immune complexes; CRP, C-reactive protein; CTA, complement activity; ESR, erythrocyte sedimentation rate; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte macrophage-colony stimulating factor; HPT, haptoglobin; Ig, immunoglobulin; IL, interleukin; ITF, interferon; LIF, leukocyte migration inhibition factor; NR, not reported; NRC, neutrophil leukocyte-related chemiluminescence; PMNs, polymorphonuclear neutrophils; S, symptomatic apical periodontitis; TNF, tumor necrosis factor.

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Figure 1. Meta-analysis results and forest plots for (A) IgA, (B) IgE, (C) IgG, and (D) IgM: evaluation between AP patients versus healthy controls.

selected studies regarding the type of IMs evaluated (31 different markers in total), which hampers and limits the present metaanalysis. Heterogeneity was also present concerning the type of AP (symptomatic, asymptomatic, or both). In this regard, studies that examined symptomatic AP have shown the strongest evidence of an increase in serum IMs (85, 86). A recent study by our group has shown that serum CRP, amyloid A, and IL-6 were signicantly increased in acute apical abscess and systemic involvement (fever, malaise, lymphadenopathy, and so on) compared with localized acute apical abscess, which lacks these signs and control patients (87). This further shows that the degree of severity of the endodontic infection may inuence the levels of systemic markers. Other studies have also shown a dose effect with the number of teeth involved (88, 89). Additionally, most included studies evaluated adult populations, but others (9092) restricted the analysis to children, which may be another source of heterogeneity. The extent to which the systemic response to AP differs according to age remains unknown. This systematic review included studies with different designs (cross-sectional, case-control, and interventional studies), contributing to the increase in data heterogeneity. Accordingly, for the meta-analysis of AP subjects before and after intervention, considerable variability was present related to the treatment intervention
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(varying from tooth extraction to nonsurgical root canal treatment, surgical root canal treatment, prescription of antibiotics, or drainage), which limits the interpretation of the meta-analysis results. Moreover, the time after the intervention also varied considerably from 7 days to 1 year, which may have contributed to the variability in outcomes between studies. Possibly as a consequence of this variability, no statistical difference was found in CRP, IgA, IgE, IgG, and IgM between AP patients before versus after endodontic treatment (Fig. 2). Noteworthy, although both qualifying studies evaluating CRP (66, 86) (Fig. 2A) showed individually statistically signicant results, the high heterogeneity (I2 = 86%) necessitated the use of a random effects model, which resulted in a nonsignicant overall estimate in the meta-analysis. In addition, inherent limitations of the cross-sectional or case-control study designs related to the meta-analysis of AP subjects versus healthy controls do not allow inferences about causality concerning the association. Furthermore, most qualifying studies presented small sample sizes and high standard deviations on serum levels of IMs for both AP and control subjects, restricting the external validity of each individual study. The possibility of patient variability on serum levels of IMs is another intrinsic limitation. In this respect, conducting the present metaanalysis represented an advantage once it was possible to look at the 1213

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Figure 2. Meta-analysis results and forest plots for (A) CRP, (B) IgA, (C) IgE, (D) IgG, and (E) IgM: evaluation between AP patients before (control) versus after treatment intervention (experimental).

pooled available data. Another notable observation is that there are few recent studies in this area, with only 3 published studies (88, 92, 93) in the last 5 years. Other methodologic features of this systematic review warrant consideration. The NOS was used to assess the methodologic quality of the included studies. The assessment of the quality of observational studies is more difcult than the assessment of the quality of randomized clinical trials and other experimental studies. Appraising observational studies with checklists/scales designed for randomized clinical trials may not be appropriate. The NOS for assessing the quality of nonrandomized studies in meta-analyses is quite comprehensive, and this instrument has been partly validated (61). Recently, some of its weaknesses have been discussed (94). Moreover, this scale is recommended by the Cochrane Non-Randomized Studies Methods Working Group. It should be noted that none of the 20 studies in this systematic review were scored 1214

9 stars (the maximum quality rate in the NOS). On the contrary, most studies revealed methodologic deciencies, ranging from 47 stars (Tables 3 and 4). Only 1 study (92) received 8 stars according to NOS criteria, which clearly reveals important methodologic limitations on studies composing the body of available evidence in this area. Most frequent methodologic aws were related to representativeness (because most studies used consecutive subjects from dental schools, hospitals, or clinics), the selection of controls (noncommunity controls or no description), and the adequacy of the follow-up of cohorts (usually with high drop-off rates). Additionally, some studies (88, 90, 92, 95, 96) did not report on the control for periodontal disease, an important potential confounder. On the other hand, a number of studies evaluating the association between periodontal disease and serum IMs simply ignore AP as a possible confounding factor in the analysis (39, 97), which might need to be revisited in future periodontal literature.
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AP is a prevalent oral local inammatory disease. The results from the present study suggest that AP is associated with systemic inammatory changes. In endodontic infections, there are several soluble bacterial products with a powerful proinammatory potential. Lipopolysaccharides, present in and released from cell walls of gramnegative bacteria, are probably the best characterized components of endodontopathic bacteria to induce cytokines and other inammatory compounds such as granulocyte-macrophage colony-stimulating factor, interferon gamma, IL-1 alpha and beta, IL-6, IL-8, macrophage chemotactic peptide-1, and TNF alpha. Host regulatory factors induced by endodontopathogenic microorganisms include cell adhesion molecules and ligands; chemokines and receptors; proinammatory cytokines, receptors, and antagonists; reactive oxygen and nitrogen intermediates and arachidonic acid metabolites; and transcription factors (59, 98). Chronic inammatory conditions may continuously stimulate the liver to synthesize increased amounts of plasma acutephase proteins (99), and, thus, the hepatic reaction may sustain inammation. In addition, certain IMs related to AP such as alpha-1-acid glycoprotein are important drug-binding proteins that have the property to decrease the free plasma concentration of a great number of drugs and, consequently, their activity (100), which can also inuence general health. In the study by Marton et al (66), the pretreatment CRP level (6.6 4.2 mg/L) was high enough to consider it as a cardiovascular risk factor according to the guidelines of the American Heart Association (101). Similarly, another study from the same group (85) found elevated whole-blood chemiluminescence, which decreased signicantly in parallel with the treatment, suggesting an activated metabolic and functional state of the peripheral blood neutrophil granulocytes in subjects with chronic AP. Another route of possible association between periapical inammation and systemic health is characterized by polymorphisms of genes encoding for cytokines and enzymes inuencing the function of immune-inammatory cells. In the presence of specic polymorphic alleles, both local and general inammatory reactions can be more intensive and the accompanying complications more severe than in the absence of the given allele (92, 98, 102). Peripheral blood monocytes of hyperinammatory type patients with periodontal disease produce 3- to 10-fold greater amounts of IL-1 beta and TNF alpha than those obtained from normal individuals (74, 103). Thus, it is reasonable to consider that systemic levels of IMs related to AP may also be inuenced by genes polymorphisms, which requires further investigation. Collectively, the ndings from the present study indicate that AP is associated with a generalized increase in systemic IMs and immunoglobulin levels when compared with healthy controls. It is also noteworthy that CRP, IgM, and IgG were the most commonly investigated markers, and all of these markers were usually elevated in patients with AP. On the other hand, although individual studies reported that the treatment of AP by tooth extraction (64, 104), apicoectomy (85), or conventional endodontic therapy (64) reduced the serum levels of IMs, ndings from the present meta-analysis do not allow conclusions regarding the effectiveness of endodontic treatment in reducing the serum levels of the different biomarkers because a high methodologic heterogeneity was present concerning interventional studies. a proatherogenic effect with a potential role in patients global vascular risk. Future large-scale prospective controlled studies designed to directly test this hypothesis are fundamental.

Conclusions
Available evidence suggest that AP is associated with increased levels of systemic inammation in humans. Meta-analysis results suggest that serum levels of IgA, IgG, and IgM are increased in humans with apical periodontitis compared with healthy controls and serum levels of CRP, IgA, IgE, IgG, and IgM were not signicantly different between patients with AP before and after the treatment intervention. There is a clear need for large-scale prospective controlled studies designed to directly test this hypothesis.

Acknowledgments
The authors thank Ms Mary Ann Williams, the librarian from the Health Sciences and Human Services Library, University of Maryland, for her valuable contribution during the literature search. The authors deny any conicts of interest related to this study.

References
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Implications for Further Research

Available evidence is limited but consistent, suggesting that AP is associated with increased levels of systemic inammation in humans. Thus, AP may add to the systemic inammatory burden of affected individuals, and it seems reasonable to consider that untreated AP may have
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JOE Volume 39, Number 10, October 2013

Systemic Levels of Inammatory Markers

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