REVIEW ARTICLE

Athina Christina Georgiou,

Apical Periodontitis Is DDS,* Wim Crielaard, MSc,
PhD,* Iakovos Armenis, MD,
Associated with Elevated PhD,†‡ Ralph de Vries, MSc,x
and Suzette V. van der Waal,
Concentrations of DDS, PhD*k

Inflammatory Mediators in
Peripheral Blood: A Systematic
Review and Meta-analysis

ABSTRACT
SIGNIFICANCE
Introduction: Apical periodontitis (AP), except for the local known consequences, may also
be a systemic burden. Circulating inflammatory mediators that are released to sustain the AP This review showed that there
lesion can in theory harm other bodily tissues. The aim of this systematic review was to is an association between
summarize the existing evidence on the influence of AP on the peripheral blood levels of apical periodontitis and
inflammatory mediators and markers of systemic stress. Methods: A search of MEDLINE- elevated inflammatory
PubMed, Embase, and Cochrane was conducted up to and including February 2019 to mediators in peripheral blood.
identify studies in 5 different languages. The Newcastle-Ottawa Scale was used for quality Therefore, apical periodontitis
assessment of the included studies. Results: Twelve of the 20 included studies were case- contributes to systemic low-
control studies, and 8 were intervention studies. The data of all the included studies were grade inflammation, which can
analyzed descriptively, whereas the data of 11 studies were available for meta-analyses. The increase the risk of other
study designs were heterogeneous. Nevertheless, the meta-analyses revealed statistically pathology.
significant differences in C-reactive protein, interleukin 6, and asymmetric dimethylarginine
levels between AP subjects and controls in peripheral blood. In addition, the concentration of
C3 complement fragment in peripheral blood was significantly lower after the treatment and
resolution of AP than before. Conclusions: The existing literature indicates that AP adds on
to systemic inflammation by elevating C-reactive protein, interleukin 6, asymmetric
dimethylarginine, and C3 levels. In order to overcome the issue of large variation between
study designs, future studies should have clear inclusion criteria, preferably larger cohorts,
From the *Departments of Preventive
adequate follow-up of all subjects, and a thorough presentation of the data to enable further Dentistry and kEndodontics, Academic
exploration of the possible burden of AP on general human health. Nevertheless, there is now Centre for Dentistry Amsterdam,
University of Amsterdam and Vrije
stronger evidence that AP contributes to low-grade systemic inflammation. (J Endod
Universiteit, Amsterdam, The
2019;45:1279–1295.) Netherlands; †Department of Cardiology,
Onassis Cardiac Surgery Centre, Athens,
KEY WORDS Greece; ‡Department of Internal Medicine,
“Laiko” Hospital, National and
Apical periodontitis; endodontics; general health; inflammatory mediators; systemic Kapodistrian University of Athens, Medical
School, Athens, Greece; and xMedical
inflammation Library, Vrije Universiteit, Amsterdam, The
Netherlands
Address requests for reprints to Ms Athina
Apical periodontitis (AP) is an inflammatory response around the root tip of teeth to an insult. Usually AP is Christina Georgiou, Department of
Preventive Dentistry, Academic Centre for
triggered by microbial infection of the root canal space, which occurs after irreversible inflammation of the
Dentistry Amsterdam, Gustav Mahlerlaan
pulp and subsequent pulp necrosis1. Clinically, AP can present itself in various ways, from asymptomatic 3004, 1081 LA Amsterdam, the
with just a periapical radiolucency on an intraoral radiograph to great clinical signs of inflammation such as Netherlands.
pain, swelling, redness, and loss of function. In case of severe discomfort, the need for treatment is E-mail address: a.c.georgiou@acta.nl
obvious and mandatory. However, often, AP is asymptomatic, and then it can remain unnoticed for years 0099-2399/$ - see front matter
unless for some other reason a radiograph is taken of the affected tooth. However asymptomatic, these Copyright © 2019 American Association
lesions (and also the symptomatic ones) may put pressure on the general health of the affected of Endodontists.
https://doi.org/10.1016/
individuals.
j.joen.2019.07.017

JOE  Volume 45, Number 11, November 2019 Apical Periodontitis and Inflammatory Mediators 1279
 Many studies in the dental field found
associations between oral inflammation and
comorbidity. In the field of periodontology,
extensive research has been performed on the
relationship between periodontitis and the
concentrations of systemic inflammatory
mediators and thus possible consequences of
periodontitis on general health. A recent large-
scale study with a cohort of 60,174
participants after screening all patients’
records of 15 years concluded that there is an
independent association of periodontitis with
atherosclerotic cardiovascular diseases2.
Another recent study linked marginal
periodontitis with Parkinson disease3, and
there are studies linking periodontitis with
adverse pregnancy outcomes, diabetes,
pneumonia, and chronic obstructive
pulmonary diseases4. Considering the
similarity of marginal and AP in terms of
inflammatory responses, it may be possible
that AP has similar consequences5.
Less extensive research has been
performed to explore those systemic
consequences of AP6. With reference to
atherosclerotic cardiovascular disease, few
studies have directly studied its possible
relation with AP. In 2006, Caplan et al7
reported that men younger than 40 years old
with AP suffered from earlier-onset coronary
heart disease than men without AP. One year
later, Frisk observed no significant relationship
between AP and coronary heart disease. In a
high-quality study of 508 patients undergoing
coronary angiography, the presence of
endodontic lesions was significantly
associated with coronary heart disease,
especially acute coronary syndromes8. Two
studies by the same research group related AP
with aortic atherosclerosis based on
computed tomographic findings9,10.
According to the definition of the World
Health Organization adopted in 1948, health is
a state of complete physical, mental, and
social well-being and not merely the absence
of disease or infirmity. Since then, a lot of
oppositions have been expressed concerning
this definition, considering the change in life
expectancy and the change in disease
burden11,12. For instance, when looking at
reference blood values of healthy, disease-free
individuals, it becomes clear that even in
disease-free humans soluble mediators of
inflammation can be detected and measured in
peripheral blood13. These inflammatory
mediators are cytokines, chemokines, acute-
phase proteins, soluble adhesion proteins, and
so on, and they are expressed to maintain
homeostasis, which is a property of a system
in which variables are regulated so that internal
conditions remain stable and relatively
1280 Georgiou et al.
constant12. These inflammatory mediators are
also found in disease because when the load
of these regulated variables is great, the
system fails to balance, which leads to
pathophysiology12. If AP does indeed modify
peripheral concentrations of inflammatory
mediators, then the reference values give
researchers an opportunity to evaluate the
influence of asymptomatic conditions such as
symptom-free AP on the systemic health.
In 2013, a systematic review and meta-
analysis on the systemic detection of AP
inflammatory mediators were conducted14.
Although the authors concluded that
inflammatory mediators including
immunoglobulins, cytokines, and asymmetric
dimethylarginine (ADMA) were increased in
humans with AP compared with controls, their
meta-analyses results supported this only with
regard to serum levels of immunoglobulin (Ig)
A, IgG, and IgM, presumably because of an
inadequate number of studies on other
mediators (ie, C-reactive protein [CRP])
available for meta-analysis. Moreover, this
systematic review failed to establish
inflammatory mediators that correspond with
the therapy. Six years later, the topic is still of
interest; we still seek more evidence regarding
whether AP can modify systemic levels of
inflammatory mediators. In the meantime,
more original scientific work has been
published, potentially modifying the
conclusions drawn from the 2013 meta-
analysis. Therefore, the aim of this systematic
review and meta-analysis was to summarize
the current existing evidence on relationships
between AP and the systemic levels of
inflammatory mediators and other stress
markers in otherwise healthy individuals.
MATERIALS AND METHODS
A detailed protocol agreed by all authors was
developed before the initiation of this review
and was registered at the PROSPERO register
(registration number CRD42019086802). The
Preferred Reporting Items for Systematic
reviews and Meta-Analyses statement15 as
well as the Cochrane handbook16 were
followed.
Focused Question
In healthy individuals, does AP add
inflammatory mediators and other systemic
stress markers to the peripheral blood
concentrations?
Inclusion and Exclusion Criteria
All prospective clinical trials, case-control
studies, and cross-sectional or cohort studies
assessing symptomatic or asymptomatic AP
were included. Studies should compare
subjects with AP before and after any
treatment or compare subjects with AP with
subjects without AP. All studies should have
been conducted on systemically healthy
adults, and the inflammatory mediators in
peripheral blood should have been quantified.
The articles should be written in the English,
Dutch, German, French, or Greek language,
which are the language skills the author team
has.
In vitro studies on cell cultures and
animals were excluded. Furthermore, studies
that evaluated local inflammatory mediators of
periapical lesions or gingival crevicular fluid
were also not considered. Studies involving
subjects with periodontitis or medically
compromised individuals were excluded.
Finally, studies quantifying only Igs were
excluded because Igs, or antibodies as they
are called, are produced to recognize and
attach pathogens, making them more of a
signaling molecule in the inflammation
procedure. Moreover, Igs continue to circulate
for months after an infection has been cleared
as part of the humoral immune system17.
Search Strategy
A thorough search of electronic literature
databases, supplemented by checking
bibliographies of review articles, was
performed by 2 independent reviewers (A.G.
and S.W.). A search of MEDLINE-PubMed,
Embase, and Cochrane was conducted on
February 4, 2019. All articles that were
available at that date have been retrieved. The
search strategy combined Medical Subject
Heading terms and text words, which can be
found in the Supplemental Table S1 (available
at www.jendodon.com). An extensive hand
search was also performed of the reference list
of the selected studies.
Screening and Selection
A 3-stage screening process was performed.
All stages (titles, abstracts, and full text) were
performed in duplicate and independently by 2
reviewers (A.G. and S.W). When a
disagreement was raised, it was resolved by
discussion, and if a consensus was not
reached, a third reviewer (W.C.) was
consulted. The articles that fulfilled all criteria
after reading the full text were selected for
detailed data processing.
Quality Assessment
The methodological quality assessment of the
included studies was performed independently
and in duplicate by 2 reviewers (A.G. and S.W.)
and was performed based on the established
JOE  Volume 45, Number 11, November 2019
 Identification
Records identified through PubMed Records identified through Embase Records identified through Cochrane
(n = 1278) (n = 1478) (n = 30)

Studies assessed by title screening after duplicates removed

Screening (n = 1676)

Studies assessed by
abstract Records excluded
(n =541) (n = 484)

Full-text articles assessed Full-text articles excluded (n = 37)

Eligibility

for eligibility
(n = 57) Reasons for exclusion reported on table 3.

Studies included in
qualitative synthesis
Included

(n = 20)

Studies included in
quantitative synthesis
(n =11)

FIGURE 1 – Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 flow diagram. A flowchart of the review search and study identification.

criteria of the Newcastle-Ottawa Scale
(NOS)18. According to the manual provided by
NOS and after calibration, quality tables were
filled in by the 2 independent reviewers. Any
differences were resolved after discussion with
a third author (W.C.).
Statistical Analysis and Assessment
of Heterogeneity
The data of the included studies, such as the
study design, population, intervention, and
outcome, were summarized in the tables.
was used. The level of significance was set at
P , .05.
RESULTS
The initial literature search resulted in 1656
unique articles (Fig. 1). At the level of full-text
evaluation, 37 articles were excluded; the
reasons for exclusion are listed in Table 1.
Finally, 20 articles met the inclusion criteria.
Two sets of articles came from the same
scientific groups50,56,57,58. Three articles
review, data from 11 studies were available for
meta-analysis.
Characteristics of the Included
Studies
Twelve of the included studies were case-
control studies, assessing peripheral blood
TABLE 1 - Reason for Exclusion of the Excluded
Research Articles: Level of Full-text Evaluation
Reason of exclusion Studies excluded
Study on medically 8,20–24

Similarities and variations were assessed by described the same clinical study and compromised
descriptive analysis. Studies assessing the therefore were merged in data extraction and individuals
25–30
same inflammatory mediators, with a similar analysis59–61. All articles included were Study on tissue
31,32–40
design, and sufficiently homogeneous in published in the English language, except for 1 Study on cells
41–45
terms of participants, methods, and that was in German59, and evidence level Outcome is genotype
interventions to provide a meaningful assessment according to the NOS was of host
46,47
Not clinical study/
summary were grouped, and a meta-analysis performed. Eight studies were published in the
literature review
was performed. Meta-analysis, if possible, last 5 years62,63,58,64–68, and 1 study had not 48
No inflammatory
was performed by software package Review been retrieved69 by a previously conducted markers tested
Manager (RevMan) Version 5.319. Statistical systematic review14 on this subject. Three Study on 49

heterogeneity was calculated as part of the authors57,64,67 were contacted, and missing thrombus aspirates
meta-analysis with a heterogeneity test, I2, data were kindly requested. Missing data were Subjects with 50,51,52

and a value .50% considered substantial average concentration and standard periodontitis
according to the Cochrane Handbook for deviations of investigated inflammatory were included.
53
Systematic Reviews of Interventions16. If mediators. Missing data were made available Unclear method
54
heterogeneity was present, a random-effects only from 1 author64. All the data were Design not matching
55
Study not on apical
model was used, and when heterogeneity extracted and analyzed descriptively in Table
periodontitis cases
was not present, a fixed-effect model 2. Of the 20 studies included in this systematic

JOE  Volume 45, Number 11, November 2019 Apical Periodontitis and Inflammatory Mediators 1281
 TABLE 2 - The Data Reported by the Included Studies
1282

Population/ Periodontal Inflammatory

Georgiou et al.

Study mean status/ Follow-up Type of markers Observations/

Study design age ± SD Type of AP smoking period (d) intervention (outcome) Sample Main results funding Limitations
Abdolsamadi CC Case: 40 A Periodontally 0 None IL-6 Serum Concentrations of IL-6 —/NR Blood taken at 1
et al69 Age: 27.8 6 3.1 healthy/nonsmoking significantly specific moment
Control: 40 correlated with and not at several
Age: 23.8 6 8.2 presence of time points
periapical lesion.
Anil et al, CC Case pg: 24 A NR/NR 0 None CIC Serum Elevation of CIC was Not specified when was Blood taken at 1
199370 Age: 24 6 5.6 observed in subjects the blood taken/ specific moment
Case pc: 21 with pg and pc in Government of and not at several
Age: 25 6 5.2 comparison with Kerala, India time points
Control: 40 control. CIC not specified
Age:24 6 5.1 Elevation of CIC at pg Method of dental
group vs pc but P . diagnosis not
.05 specified
Boucher CC Case AAA: 10 A/S Periodontally 2 and 8 Antibiotics/teeth CRP Serum 13/23 subjects with AP No statistical analysis/ Only 2 subjects were
et al71 Age: NR healthy/NR extraction* (56.5%) presented US Public Health followed after
Case CAA: 13 increased CRP. Service grant treatment.
Age: NR Sample size
Control: 7 Method to measure
Age: NR CRP
Cotti et al57 CC Case: 20 NR Periodontally 0 None IL-1, IL-2, IL 6, TNF-a, Serum Significant increase in No report of actual Only male subjects
Age: 35 6 5 healthy/NR and ADMA serum levels of IL-1, concentrations and
Control: 20 IL-2, IL-6, and SD of IL-1, -2, and
Age: 27 6 3 ADMA compared -6/Fondazione
with controls Banco di Sardegna
No difference TNF-a
Cotti et al58 CC Case: 41 NR Periodontally 0 None IL-2, TNF-a, ROS, and NR AP may cause early TNF-a although
Age: 31 6 5.71 healthy/NR ADMA endothelial reported in methods
Control: 40 dysfunction. not presented in
Age: 31 6 5.71 AP in men may influence results/Fondazione
the metabolism of Banco di Sardegna
NOS.
AP in women appears to
implicate a more
detrimental
mechanism.
The blood levels of ROS
were found
significantly elevated
only in women with
JOE  Volume 45, Number 11, November 2019

AP.
Garrido CC Case: 27 A Periodontally 0 None hsCRP, IL-6, IL-10, Serum Serum hsCRP levels —/National Fund of Only median values
et al64 Control: 28 healthy IL-12p70, MMP-8, significantly higher in Chile for Scientific reported for hs-
Age: 18–40 /smokers sVCAM-1, sICAM-1, AP group than in Development CRP, Il-6, MMP-8,
included and sE-selectin controls sVCAM-1, and
Levels of IL-6, MMP-8, sICAM-1
and sE-selectin Smokers included
significantly higher in
AP group than in
controls
Il-10 and IL-12p70 no
statistically
significant
differences
Gomes et al65 CC Depression: 24 AL NR/smokers included 0 Extraction AOPP Plasma Elevated levels of root Results were not No information about
No depression: NOx canal LPS in AP are analyzed and the periodontal
23 LOOH associated with grouped according status of the patients

(continued on next page )

 TABLE 2 - Continued
JOE  Volume 45, Number 11, November 2019

Population/ Periodontal Inflammatory

Study mean status/ Follow-up Type of markers Observations/
Study design age ± SD Type of AP smoking period (d) intervention (outcome) Sample Main results funding Limitations

With AP or depression and to the results of

without lowered quality of case/control but into
life, increased NOx, elevated LPS and
and lower LPS/NR
hypernitrosylation
Attributable association
between depression
and AP
Harjunmaa CC AP group: NR NR/nonsmokers 0 Unknown CRP, AGP plasma No difference in CRP —/Bureau for Global Pregnant women but
et al66 1–3 apical lesions: 215 and AGP in the first Health; US Agency healthy at
.3 apical half of the pregnancy for international recruitment and all
lesions: 26 Development; Bill & provided with
Control: 783 Melinda Gates antimalarial
Foundation; Finnish medication
Cultural Foundation; Blood taken also at 36
Finnish Dental weeks, but because
Society Apollonia the prevalence of
chorioamnionitis and
intervillositis
increases as the
pregnancy
progresses, the 36-
week blood levels
have not been
included
AP lesions diagnosed
on OPTs
Inchingolo I AP group: 33 A Periodontally 0, 30, and 90 Endodontic d-ROMs, BAP Plasma Baseline increased d- —/NR
et al62 (30–68) healthy/nonsmokers treatment ROMs and low BAP
Control group: 103 in AP subjects
(30–68) Significant lower BAP of
AP group vs control
before and 30 days
after treatment
There is a relationship
Apical Periodontitis and Inflammatory Mediators

between AP and
oxidative stress.
Jakimiak I Chronic PA: 20 A/S Periodontally 0, 1, and 7 Extractions, CRP Serum In chronic PA, CRP 10– It is concluded that if A range of the CRP is
et al63 Acute PA: 20 healthy/NR pus drainage, 40 mg/L in baseline CRP exceeds 100 presented and no
Age: 25–40 and antibiotic after 7 days back to mg/L, other causes data of statistical
prescription normal than odontogenic analysis.
In acute PA, CRP did infection should be No healthy controls
not exceed 80 mg/L considered./NR Different types of
and decreased treatment
significantly after 7
days, remaining
above normal
No increase in CRP
because of surgical
procedures
Kettering I AP group: 35 S NR/NR 0 and NR Endodontic IC and C3 Serum Significant difference The time of follow-up 1 patient had
et al56 Age: 12–53 (31.6) treatment/ between all acute not mentioned/NR rheumatoid arthritis.
Control group: 30 extraction patients and the 8 of the 13 patients with
Age: 24–62 (38.6) control population in elevated levels of IC
1283

(continued on next page )

 1284

TABLE 2 - Continued

Population/ Periodontal Inflammatory

Georgiou et al.

Study mean status/ Follow-up Type of markers Observations/

Study design age ± SD Type of AP smoking period (d) intervention (outcome) Sample Main results funding Limitations

IC and C3 returned for follow-

Significant difference up, 77% dropout (of
between baseline group of 35).
and follow-up of 8 For this reason, follow-
AP patients in the up data are highly
mean levels of IC biased.
and C3 Controls not properly
screened; only
absence of
abscesses was
assessed.
Kimak et al67 CC Case: 43 A Periodontally 0 None IL-6, TNF-a, LpPLA2, Unclear In patients with AP Only 1 measurement/ 9 patients receiving
Age: 61 (32–69) healthy/nonsmoking and hsCRP together with aging, NR antihypertensive
Control: 20 the size of the CAP medication were
Age: 40 (32–50) lesion and the included.
concentration of The size of the lesion
inflammatory was measured in
markers and mm in intraoral
LpPLA2 mass radiographs.
increase. Not age-matched
control group, not of
the same population
Marton et a59 I AP group: 36 A/S NR/NR 0, 7, and 90 Surgical AAT, AMG, CRP, C3, Serum Significant increase on No healthy control/NR Sample size and mean
Marton et al60 14 male/22 females endodontic CER, HPT, CTA, AAT, CRP, and CRP dropout rates
Marton & Kiss61 Mean age: 28.1 and treatment lymphocytes, and at baseline (21.2% at 7 days
25.2 NRC compared with the and 54.5% at 3
reference value months)
Significant decrease of
AAT and CER in 7
days, and CRP not
altered
Significant decrease in
CRP after 3 months
Matsushita CC Case: 10 A Periodontally 0 None IL-1a, IL-1b, IL-2, IL-6, Serum All cytokines except No healthy control Limited sample size
et al31 Age: NR healthy/NR IL-8, TNF-a, ITF-g, TNF-a and GM-CSF This study concentrates Many clinical values
Control: 6 G-CSF, and GM- were undetectable. on in vitro bacterial were under the
Age: NR CSF TNF-a and GM-CSF stimulation of detection limits.
were detected in a cytokines/Ministry of
JOE  Volume 45, Number 11, November 2019

serum sample from Education, Science

1 subject. and Culture of Japan
.
Minczykowski I AP group: 20 A/S NR/NR 0 and 14 Extraction H2O2 and O2 Plasma Baseline increased PMNs were stimulated Limited sample size
et al72 Age:19–49 (33.9) production by production of H2O2 in vitro/NR PMNs stimulated in vitro
Control group: 20 stimulated and and O2 in AP
Age: NR unstimulated PMNs samples vs control
Significant decrease on
H2O2 and O2
production by
unstimulated PMNs
after treatment
Ren et al73 I AP group: 14 S NR/smokers 0 and 7 Extraction, endodontic CRP Serum 60% of the subjects Patients were not Sample size, drop-off
Age: 35.7 and treatment, or presented with checked for other rate at follow-up
Control group: 10 nonsmokers pus drainage all increased CRP, oral infections./ Periodontal disease not
Age: NR combined with which is significant Eastman controlled

(continued on next page )

JOE  Volume 45, Number 11, November 2019

TABLE 2 - Continued

Population/ Periodontal Inflammatory

Study mean status/ Follow-up Type of markers Observations/
Study design age ± SD Type of AP smoking period (d) intervention (outcome) Sample Main results funding Limitations

antibiotic to healthy subjects. Department of

prescription 90% of the subjects had Dentistry and Orion
undetectable CPR Diagnostica
levels at 1-week
follow-up.
Sirin et al68 CC AP group: 100 A/S Periodontally 0 None hsCRP Serum hsCRP levels of —/NR
Age: 40618 healthy/nonsmokers subjects with AP
Control group: 40 were significantly
Age: 42615 higher than the levels
of control group.
Torabinejad CC AP group: 30 A Periodontally 0 and 365 Endodontic IC and C3 Serum No statistical difference Unknown retention Examination only at
et al50 Mean age: 35 (18–64) healthy/NR treatment in serum levels of IC rate/private baseline and only the
Control group: 30 and C3 between AP contribution of Dr subjects with
Age: 38.6 (24–69) subjects and John G. Hockin and elevated blood
controls Endodontic concentrations of IC
Research Fund and C3 were
followed up 1 year
after treatment.
No follow-up for
controls

A, asymptomatic apical periodontitis; AAA, acute alveolar abscess; AAT, alpha-1-antitrypsin; ADMA; asymmetrical dimethylarginine; AGP, a-acid glycoprotein; AMG, alpha-2-macroglobulin; AOPP, advanced oxidation protein products; AP, apical
Apical Periodontitis and Inflammatory Mediators

periodontitis; BAP, biological antioxidant potential; CAA, chronic alveolar abscess; CAP, chronic apical periodontitis; CC, case control; CER, oxidative activity of ceruloplasmin; CIC, circulating immune complex; CRP, C-reactive protein; CS, cross-
sectional; CTA, compliment activity; d-ROMs, reactive oxygen metabolites; ESR, erythrocyte sedimentation rate; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HPT, haptoglobin; hsCRP,
high-sensitivity CRP; H2O2, hydrogen peroxide; I, interventional study; IL, interleukin; ITF, interferon; LOOH, lipid peroxide; LpPLA2, lipoprotein-associated phospholipase A2; MMP-8, matrix metalloproiteinase-8; NA, not applicable; NOx, nitric oxide
metabolites; NR, not reported; NRC, neutrophil leukocyte-related; OPT, orthopantomogram (chemiluminescence); pc; periapical cyst; pg, periapical granuloma; PMN, polymorphonuclear neutrophil; S, symptomatic apical periodontitis; sE-selectin,
soluble E-selectin; sICAM-1, soluble intercellular adhesion molecule; sVCAM-1, soluble vascular adhesion molecule; TNF-a, tumor necrosis factor alpha.
*This study followed only 2 subjects after intervention.
1285
TABLE 3 - Newcastle-Ottawa Scale Criteria Methodologic Quality Assessment of Cohort and Interventional Studies

Inchingolo Jakimiak Kettering Marton Minczykowski Ren

Criteria et al62 et al63 et al56 et al59–61 et al72 et al73
Selection
Representativeness — — — — — —
of the exposed cohort
Selection of the * * — — * —
nonexposed cohort
Ascertainment of exposure * * * * * *
Demonstration that * * * — * *
outcome of interest was
not present at start of study
Comparability
Comparability of cohorts ** — * * * —
on the basis of the
design or analysis
Outcome
Assessment of outcome * — * * * *
Was follow-up long enough * — — * * —
for outcomes to occur
Adequacy of follow-up * * — — — —
of cohorts (,20%)
Total awarded stars 8 4 4 4 6 3

concentrations of inflammatory mediators in antibiotic administration, endodontic Description of Study Population

AP subjects in comparison with control
subjects. Eight were interventional studies,
assessing inflammatory mediators before and
after treatment. The treatments varied among
the studies and included pus drainage,
treatment, surgical endodontic treatment or
extraction, and sometimes a combination of
treatments. The quality (Tables 3 and 4) of the
included studies also varied and was rated
from 3 to 8 stars according to the NOS criteria.
Of the 20 studies included, 6 investigated
subjects with asymptomatic AP, 3 investigated
symptomatic AP, 8 studied both symptomatic
and symptomatic AP, and 3 did not report on
the type of AP. The periodontal status of the

TABLE 4 - Methodologic Quality Assessment of Case-control and Cross-sectional Studies

Abdolsamadi Anil Boucher Cotti Cotti Garrido Gomes Harjunmaa Kimak Matsushita Sirin Torabinejad
Criteria et al69 et al70 et al71 et al57 et al58 et al64 et al65 et al66 et al67 et al31 et al68 et al50
Selection
Is the case * * * * * * — * * * * *
definition
adequate
Representativeness — — — * * * — * * — * —
of the cases
Selection * — — — — * — * — — * —
of controls
Definition * * * * * * — * * * * *
of controls
Comparability
Comparability ** ** — ** ** ** * ** * * ** **
of cases and
controls on the
basis of the
design
or analysis
Outcome
Ascertainment * * * * * * * * * * * *
of exposure
Same method of * * * * * * * * * * * *
ascertainment
for cases and
controls
Nonresponse rate NA NA NA NA NA NA NA NA NA NA NA NA
Total awarded stars 6 6 4 7 7 8 3 8 6 5 8 6

NA, not applicable.

1286 Georgiou et al. JOE  Volume 45, Number 11, November 2019
FIGURE 2 – A forest plot of comparison: AP versus control. (A ) CRP severe PAI, (B ) CRP moderate PAI, (C ) CIC, (D ) ADMA, (E ) ROS, and (F ) IL-6.

JOE  Volume 45, Number 11, November 2019 Apical Periodontitis and Inflammatory Mediators 1287
FIGURE 3 – A forest plot of comparison: baseline versus follow-up, outcome. (A ) CRP and (B ) C3.
subjects was examined and characterized as
“healthy” in 13 studies, whereas for the rest
nothing was reported on the periodontal
status. Four studies included only
nonsmokers, 13 studies did not report on the
smoking habits of participants, and 3 studies
included smokers.
Meta-analyses of Inflammatory
Mediators: AP Subjects Versus
Controls
Of the 7 studies evaluating acute-phase
CRP59–61,63,64,67,68,71,73, results from 4 studies
were available for meta-analysis for the AP
group versus the control group, and depending
on the size and number of lesions, 2 meta-
analyses were performed including similar
subject groups of each study; namely, severe or
moderate periapical index (PAI) subjects with
AP (severe PAI) had significantly higher CRP (P
, .0001) than controls, whereas low
heterogeneity was present (I2 5 36%, Fig. 2A).
Subjects with AP (moderate PAI) had
significantly higher CRP (P 5 .0002) than
controls, whereas no heterogeneity was
present (I2 5 0%, Fig. 2B). Of the 3 studies
performing circulating immune complex (CIC)
analysis50,56,70, there were data from 2 studies
available for meta-analysis (Fig. 2C) and there
was no difference between AP subjects and
controls (P 5 .34), but there was great
heterogeneity between the studies (I2 5 98%).
Two studies coming from the same scientific
group evaluated the endogenous inhibitor of
nitric oxide ADMA, which is a strong predictor of
adverse cardiovascular events and were
available f or meta-analysis (Fig. 2D), resulting in
1288 Georgiou et al.
a statistically significant difference (P 5 .0008)
between AP subjects and controls with no
heterogeneity present. Additionally, 2 studies
examined concentrations of reactive oxygen
species (ROS) (Fig. 2E), and no difference was
found with great heterogeneity (I2 5 100%)
present. Finally, data from 2 studies evaluating
IL-6 were available for meta-analysis (Fig. 2F),
resulting in a statistical difference (P , .00001)
between AP subjects and controls with no
heterogeneity present (I2 5 0%).
Meta-analyses of Inflammatory
Mediators: AP Subjects before
Versus after Treatment
Of the 7 studies assessing CRP, 2 included a
comparison between baseline and the follow-
up period, and the data were available for
meta-analysis with no significant difference
between the groups (P 5 .40) and high
heterogeneity present (Fig. 3A). Furthermore,
available data from 2 studies that evaluated C3
levels before and after treatment showed
significant statistical differences (P 5 .008)
between groups and no heterogeneity
(Fig. 3b).
DISCUSSION
Over the past 5 to 6 years, the possible
consequences of AP in general health have
received great interest from scientists. Opinion
pieces have been published74–76, and
research grants on this particular topic have
been installed. The current systematic review
and meta-analysis were conducted with the
aim to evaluate whether the continuous
attention to this topic has resulted in new
insights. Indeed, there is new published
evidence that there is a certain systemic
burden in AP subjects. The novel data available
made the conduction of a meta-analysis of the
levels of CRP, IL-6, and ADMA between AP
patients and controls possible and showed
differences between the groups. Also, C3
concentrations in interventional studies
differed significantly between baseline and
follow-up. Consequently, an objective
measure of AP resolution besides clinical/
radiologic markers emerged. In the future, C3
level measurement may allow direct
comparison of the effectiveness of different
treatment regimens both on the research and
clinical levels. Besides the results of the meta-
analyses, other levels of inflammatory
mediators (IL-2, CIC, tumor necrosis factor
alpha, and different oxidative stress markers) in
subjects with AP were elevated (Table 2) in
untreated AP cases. It is worth noting that the
recent studies were also of a higher
methodological quality, which allows us to
interpret these results with more confidence.
Although the quality of the studies
varied from 3 to 8 stars (Tables 3 and 4), there
was low heterogeneity between the studies
that investigated peripheral CRP
concentrations. Therefore, the findings
indicate that AP can be a burden to systemic
health. CRP is an acute-phase reactant mainly
produced by hepatocytes. CRP also
possesses an important physiological role as
an inflammatory mediator that activates
various cell types and controls complement
activation77. It has been directly linked to
atherosclerotic vascular disease; it may attach
to low-density lipoprotein, 1 of the major
JOE  Volume 45, Number 11, November 2019
contributors to atherosclerotic plaque
formation. Moreover, it has been located
inside atherosclerotic plaques, where it
presumably promotes their formation and
enhances inflammation of the blood vessel
walls, rendering plaques unstable and prone
to rupture78. Such events are responsible for
acute vascular occlusion occurring in acute
coronary syndromes or acute cerebrovascular
ischemic strokes. Indeed, higher steady-state
CRP values have been related to an increased
risk of acute cardiovascular events, and it is
considered to be the only valid standardized
biomarker for predicting cardiovascular
disease78.
Although CRP values ,10 mg/L
effectively rule out significant acute
inflammation and may be considered
normal13, they do not exclude chronic or
systemic low-grade inflammation. Systemic
low-grade inflammation may result in minor
steady-state elevation of CRP within the range
of 3–10 mg/L, whereas the normal values are
considered to be ,3 mg/L79. These values
have been related to an increased risk of
cardiovascular events; namely, 1–3 mg/L is
considered intermediate risk and .3 mg/L
high risk64,79. The magnitude of the CRP
increase observed in the included studies
increases the risk for cardiovascular disease, a
finding consistent with the observed
association between AP and atherosclerotic
cardiovascular disease.
On the other hand, the current meta-
analysis failed to confirm a CRP reduction after
AP treatment. This may be explained by the
great variation in study design regarding AP
treatments, the intensity of the periapical
inflammation because asymptomatic and
symptomatic cases were both included, and
the variation in the follow-up time points.
Future clinical studies should address these
issues more thoroughly to be able to
investigate whether CRP levels will decrease
after AP treatment.
Furthermore, the meta-analysis
revealed significantly increased levels of IL-6
circulating in the blood of subjects with AP in
comparison with the control groups. IL-6 is a
multifunctional immunoregulatory cytokine that
is produced by several kinds of immune cells69
and has a vital role in the host defense.
Dysregulated production of IL-6 may act
proinflammatory and initiate autoimmune
diseases and chronic inflammation80. It should
also be noted that IL-6 regulates, among other
mediators, the production of CRP and thus
contributes to low-grade systemic
inflammation81.
The current meta-analysis showed a
significant reduction of C3 values of AP
JOE  Volume 45, Number 11, November 2019
subjects after therapy with low heterogeneity
between the studies; however, the quality of
the studies was characterized as mediocre (4
stars). The complement C3 is a protein
network of the innate immune system. Its
activation by extrinsic or intrinsic stimuli
ultimately results in target cell lysis and
phagocyte accumulation82. Its C3 fragment,
also considered to be an acute-phase
reactant, has been related to metabolic
syndrome, diabetes mellitus, smoking, and
atherosclerotic cardiovascular disease82,83.
Higher serum values have been associated
with higher cardiovascular risk, even on top of
other existing risk factors82,83. The reduction of
C3 after AP treatment seems to confirm the
effectiveness of the available therapeutic
approaches to AP in suppressing systemic
inflammation and introduces a possible new
prospective marker of systemic response to
AP therapy while raising the possibility of the
cardioprotective role of AP treatment. The last
notion should be validated in future
prospective studies.
The current review confirmed that AP
subjects have significantly higher plasma
ADMA levels compared with controls. ADMA is
a modified amino acid that inhibits nitric oxide
synthases, the enzymes responsible for the
production of nitric oxide. Endothelial nitric
oxide synthase is indispensable for proper
endothelial function; endothelial dysfunction,
characterized by endothelial nitric oxide
synthase down-regulation/inhibition, is a
hallmark of atherosclerotic cardiovascular
disease84,85. Plasma ADMA levels are
increased in response to inflammatory stimuli
and, not surprisingly, have emerged as a risk
factor for coronary heart disease on top of
other risk factors86,87.
The current review showed that there is
no significant difference between the systemic
stress indicated by levels of ROS of AP
subjects and the control groups with great
heterogeneity of the data. However, both of
the included studies were of good quality.
Although ROS plays an important role in
immune-mediated defense and serves as cell
signaling molecules, it can also cause damage
in DNA, lipids, and proteins. Antioxidant
molecules serve as regulators and modulate
the concentration of ROS. In recent years, the
role of ROS in aging, vascular diseases, and
other diseases has been explored88. Four
studies58,62,65,72 studied the effect of AP on
oxidative stress or on the increased production
of oxidative species. Fundamental research
has shown that oxidative stress may have
proinflammatory effects by activating nuclear
factor kappa B, which increases the
expression of proinflammatory cytokines,
Apical Periodontitis and Inflammatory Mediators
chemokines, and cell adhesion molecules89.
The concentration of hydrogen peroxide
(H2O2), which is an ROS, is not static or even at
a steady state and can vary with physiological
conditions. To accurately estimate the H2O2
concentration in blood, after blood is drawn, it
is important to remove the blood cells as
quickly as possible by centrifugation. This
prevents H2O2 production and H2O2 removal
by soluble proteins and small molecules in the
blood collection tube90. Heterogeneity of the
data (I2 5 100%) is explained by differences in
handling of the blood samples in combination
with the use of different assays. One study
used serum58, another study used plasma62,
and a third study measured the H2O2
production by polymorphonuclear leukocytes
in vitro. Future studies should include
techniques of tracing more stable products of
oxidation plus the concentrations of
antioxidants also could be taken into
consideration.
A limitation of the current review is that
we in general had to work with high variation in
study designs58. In general, heterogeneity
hinders the evaluation of results and therefore
the sturdiness of the final conclusions. Great
variation in methods of analysis and the
missing data of some studies have resulted in
another limitation—the inclusion of only 11
studies in the meta-analyses.
Future studies should be conducted in a
more similar way with stricter inclusion criteria,
similar methods, and clearer presentation of
the data. We would like to make a few
suggestions. In the current review, it was
decided that only studies on healthy subjects
would be included to gain insight into the
possible impact of AP on general health. As a
result, studies evaluating the effect of AP on
the health of diseased subjects were excluded
(Table 1). Although the dental field is very
interested in the systemic consequences of AP
on general health, until now many studies
mostly evaluated relationships between AP
and existing pathology. Because of the
complexity of different diseases and
medication often is used to control the
condition, the exact burden of AP remains
unknown. Existing disease can confound the
additional effect that AP may have on health.
Another important factor that should be
considered during subjects’ inclusion is the
psychological status of the subjects. Mental
disorders are quite common nowadays, with
their prevalence ranging between 18.1% and
36.1% depending on the severity and type of
disorder studied91. According to World Health
Organization prognostics, depression is going
to be the world’s second most frequent cause
of disability by 203092. It is also considered a
1289
taboo or not of relevance and is often not
shared during medical history registration.
However, in recent years, the hypothesis that
proinflammatory cytokines induce depressive
symptoms has been scientifically
established93. Furthermore, many studies
report a significant influence of
antidepressants on proinflammatory/anti-
inflammatory cytokine balance94. With of all of
these factors being considered, psychological
status can be a confounding factor when
peripheral blood concentrations of
inflammatory mediators are examined;
therefore, subjects with psychological
problems, treated or not, should ideally not be
included, or they should be considered as a
separate group.
Smoking may also be a confounding
factor, with some studies reporting only on
nonsmokers, some on smokers, and several
studies not reporting on the smoking status of
the participants. A recent study evaluating the
concentration of inflammatory mediators in the
dental pulp of smokers and nonsmokers has
concluded that smoking compromises the
immunoregulatory response of the pulp. There
is evidence that nicotine inhibits the production
of tumor necrosis factor alpha, IL-2, IL-1, and
other inflammatory mediators95. Furthermore,
another study on radiographs found a
statistically significant association between
smoking and AP additional to a delayed bone
healing process among smokers96. These
conclusions match with the study of Nile et al97
in which a lower reduction of the IL-17A:IL-17E
ratio compared with nonsmokers was
observed, negatively affecting the resolution of
the inflammatory response. Because the
immune response is suppressed in smokers,
future studies should include only nonsmokers
or possibly larger cohorts with a separate
smoking subject group in order to explore the
possible differences between the groups.
In the initiation of this review, the
participation of subjects with marginal
periodontitis was a reason for exclusion. As
mentioned earlier, the effect of periodontitis on
the concentration of inflammatory mediators in
the blood has been extensively
investigated4,97. However, there were several
studies included in this review in which the
periodontal status of the participants was not
reported. It is advisable that future studies
should screen participants for marginal
periodontitis and include only subjects with
healthy gingiva to figure out what the actual
contribution of AP to health or existing
pathology is although the recruitment and
1290 Georgiou et al.
inclusion of subjects would become more
tedious.
Regarding the methods, a few
comments can be given to acquire more
similar data. Treatment and follow-up varied
greatly between studies. In the included
interventional studies, different treatments
were performed, ranging from antibiotic
administration, pus drainage, and endodontic
treatment to surgical endodontic treatment.
Different treatments can give various
outcomes on the inflammatory responses.
Furthermore, various treatments have different
success rates, with some of them having an
outcome that can only be evaluated several
months later (surgical and nonsurgical
endodontic treatment) and others offering relief
of the acute symptoms (tooth extraction and
pus drainage).
The follow-up periods ranged from 1
day to 1 year. It would be very interesting to
follow the progression of the resolution of AP
by measuring multiple times within 1 subject.
The time point of the day of sampling in the
intervention studies should also be
considered. The concentrations of
inflammatory mediators tend to vary as a result
of the circadian rhythm, and, therefore, when
measuring multiple times within a subject, the
time points should be comparable98.
Sample processing is also an important
issue to consider because a majority of the
concentrations of mediators are considerably
different when measured in serum or
plasma99. Whole blood is composed of blood
cells suspended in blood plasma. Plasma
constitutes 55% of blood fluid and is mostly
water (92% by volume). Plasma also contains
proteins, glucose, mineral ions, hormones,
carbon dioxide, soluble mediators, and clotting
factors. Blood serum is plasma without most of
the clotting factors and is obtained after
clotting of the whole blood sample for about 30
minutes after blood draw. Subsequently, the
clotted blood is centrifuged to remove the
cellular components. When obtaining blood
serum, during the clotting phase,
thrombocytes can still release a wide range of
inflammatory mediators (eg, cytokines and
soluble adhesion molecules)100. This ex vivo
release during sample coagulation/preparation
can contribute to the serum levels99. In the
included articles of the current review, mostly
serum was obtained, although in some articles
the type of sample, serum or plasma, was not
reported. However, for future studies, we think
that it is important to agree on a standardized
sampling procedure and to present detailed
methodological descriptions. Differences in
sample preparation can explain contradictory
findings99 and, hence, the heterogeneity
between obtained data.
To overcome the lack of large-scale
studies, in theory combining data from multiple
smaller studies may help to identify patterns
among study results. To be able to do so,
besides similar inclusion criteria and methods,
the data should also be presented in a clear
way with at least the sample size, averages
and standard deviations, tables, and graphs
with captions.
CONCLUSIONS
From the current systematic review with meta-
analysis, it can be concluded that AP subjects
have higher peripheral blood values of CRP
than control subjects. Other associations
between the presence of AP and elevated
levels of systemic inflammatory mediators
were observed when evaluating ADMA and IL-
6 serum values in AP subjects versus control
subjects. Moreover, the concentration of C3
levels in peripheral blood was significantly
lower after the treatment and resolution of AP
than before. No significant difference between
the systemic stress expressed in
concentrations of ROS or CIC of AP subjects
and the control groups was found. The
conclusions regarding CIC and ROS are based
on heterogeneous data, which may hamper
the soundness of these results. Future studies
should have a design with clear inclusion
criteria, preferably larger cohorts, adequate
follow-up of all subjects, and complete
presentation of the data in order to further
explore the possible impact of AP on general
human health. In conclusion, there is strong
evidence that AP contributes to systemic low-
grade inflammation.
ACKNOWLEDGMENTS
The authors thank Prof Marcela Herna ndez
Ríos for making additional unpublished data
requested available.
The authors deny any conflicts of
interest related to this study.
SUPPLEMENTARY MATERIAL
Supplementary material associated with this
article can be found in the online version at
www.jendodon.com (https://doi.org/10.1016/
j.joen.2019.07.017).
JOE  Volume 45, Number 11, November 2019
 REFERENCES
1. Kakehashi S, Stanley HR, Fitzgerald RJ. The effects of surgical exposures of dental pulps in
germ-free and conventional laboratory rats. Oral Surg Oral Med Oral Pathol 1965;20:340–9.

2. Beukers NG, van der Heijden GJ, van Wijk AJ, Loos BG. Periodontitis is an independent risk
indicator for atherosclerotic cardiovascular diseases among 60 174 participants in a large dental
school in the Netherlands. J Epidemiol Community Health 2017;71:37–42.

3. Chen CK, Wu YT, Chang YC. Periodontal inflammatory disease is associated with the risk of
Parkinson’s disease: a population-based retrospective matched-cohort study. PeerJ
2017;5:e3647.

4. Sabharwal A, Gomes-Filho IS, Stellrecht E, Scannapieco FA. Role of periodontal therapy in

management of common complex systemic diseases and conditions: an update. Periodontol
2000 2018;78:212–26.

5. Jansson L. Relationship between apical periodontitis and marginal bone loss at individual level
from a general population. Int Dent J 2015;65:71–6.
6. Segura-Egea JJ, Martin-Gonzalez J, Castellanos-Cosano L. Endodontic medicine: connections
between apical periodontitis and systemic diseases. Int Endod J 2015;48:933–51.
7. Caplan DJ, Chasen JB, Krall EA, et al. Lesions of endodontic origin and risk of coronary heart
disease. J Dent Res 2006;85:996–1000.

8. Liljestrand JM, Mantyla P, Paju S, et al. Association of endodontic lesions with coronary artery
disease. J Dent Res 2016;95:1358–65.
9. Petersen J, Glassl EM, Nasseri P, et al. The association of chronic apical periodontitis and
endodontic therapy with atherosclerosis. Clin Oral Investig 2014;18:1813–23.
10. Glodny B, Nasseri P, Crismani A, et al. The occurrence of dental caries is associated with
atherosclerosis. Clinics (Sao Paulo) 2013;68:946–53.

11. Huber M, Knottnerus JA, Green L, et al. How should we define health? BMJ 2011;343:d4163.
12. Zaura E, ten Cate JM. Towards understanding oral health. Caries Res 2015;49(Suppl 1):55–61.

13. Calder PC, Ahluwalia N, Albers R, et al. A consideration of biomarkers to be used for evaluation
of inflammation in human nutritional studies. Br J Nutr 2013;109(Suppl 1):S1–34.
14. Gomes MS, Blattner TC, Sant’Ana Filho M, et al. Can apical periodontitis modify systemic levels
of inflammatory markers? A systematic review and meta-analysis. J Endod 2013;39:1205–17.

15. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and
meta-analyses: the PRISMA statement. BMJ 2009;339:b2535.

16. Higgins JP, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions
Version 5.1.0 [updated March 2011]. London, UK: The Cochrane Collaboration; 2011.
17. Parham P. The Immune System. 4th ed. Abingdon, UK: Taylor & Francis Group, LLC; 2015.
p. 231–64.

18. Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the
quality of nonrandomized studies in meta-analyses. Available at: http://www.ohri.ca/programs/
clinical_epidemiology/oxford.htm. Accessed July, 31 2018.

19. Review Manager (RevMan). [Computer program]. Version 5.3. Copenhagen, Denmark: The
Nordic Cochrane Centre, The Cochrane Collaboration; 2014.

20. Al-Zahrani MS, Abozor BM, Zawawi KH. The relationship between periapical lesions and the
serum levels of glycosylated hemoglobin and C-reactive protein in type 2 diabetic patients. Saudi
Med J 2017;38:36–40.

21. Chudek J, Niedzielska I, Kowol I, et al. Odontogenic-related micro inflammation in patients with
hypertension and chronic kidney disease. J Hypertens 2010;28:e271–2.
22. Rashmi N, Galhotra V, Goel P, et al. Assessment of C-reactive proteins, cytokines, and plasma
protein levels in hypertensive patients with apical periodontitis. J Contemp Dent Pract
2017;18:516–21.
23. Vidal F, Fontes TV, Marques TV, Goncalves LS. Association between apical periodontitis lesions
and plasmatic levels of C-reactive protein, interleukin 6 and fibrinogen in hypertensive patients.
Int Endod J 2016;49:1107–15.
24. Motta AC, Furini RB, Simao JC, et al. The recurrence of leprosy reactional episodes could be
associated with oral chronic infections and expression of serum IL-1, TNF-alpha, IL-6, IFN-
gamma and IL-10. Braz Dent J 2010;21:158–64.

JOE  Volume 45, Number 11, November 2019 Apical Periodontitis and Inflammatory Mediators 1291
 25. Araujo-Pires AC, Biguetti CC, Repeke CE, et al. Mesenchymal stem cells as active prohealing
and immunosuppressive agents in periapical environment: evidence from human and
experimental periapical lesions. J Endod 2014;40:1560–5.

26. Araujo-Pires AC, Francisconi CF, Biguetti CC, et al. Simultaneous analysis of T helper subsets
(Th1, Th2, Th9, Th17, Th22, Tfh, Tr1 and Tregs) markers expression in periapical lesions reveals
multiple cytokine clusters accountable for lesions activity and inactivity status. J Appl Oral Sci
2014;22:336–46.
27. Berryhill AA, Handlers J, Schonfeld SE. Immunoglobulins and complement in the chronic
interradicular lesions of the primary teeth. Pediatr Dent 1983;5:200–3.

28. Miller GA, DeMayo T, Hutter JW. Production of interleukin-1 by polymorphonuclear leukocytes
resident in periradicular tissue. J Endod 1996;22:346–51.

29. Tasman F, Dagdeviren A, Kendir B, et al. Endothelial cell and stromal antigens in human
periapical granulation tissue. J Endod 2000;26:81–4.
30. Gazivoda D, Vucevic D, Majstorovi I, et al. Characterization of T regulatory cells in human
periapical lesions. Eur J Immunol 2009;39:S432.

31. Matsushita K, Tajima T, Tomita K, et al. Inflammatory cytokine production and specific antibody
responses against possible causative bacteria in patients with multilesional periapical
periodontitis. J Endod 1998;24:817–21.

32.  M, Gazivoda D, Majstorovic

Colic  I, et al. Immunomodulatory activity of IL-27 in human
periapical lesions. J Dent Res 2009;88:1142–7.

33.  M, Vasilijic
Colic  S, Gazivoda D, et al. Interleukin-17 plays a role in exacerbation of inflammation
within chronic periapical lesions. Eur J Oral Sci 2007;115:315–20.
34. Euler GJ, Miller GA, Hutter JW, D’Alesandro MM. Interleukin-6 in neutrophils from peripheral
blood and inflammatory periradicular tissues. J Endod 1998;24:480–4.

35. Hoenig JF, Rordorf-Adam C, Siegmund C, Erard F. Measurement of interleukin 1 alpha and 1
beta (IL-1 alpha and IL-1 beta) in human cystic lesions of the jaw. Implications for the
pathogenesis of radicular cysts. Bull Group Int Rech Sci Stomatol Odontol 1991;34:67–72.

36. Martinho FC, Chiesa WM, Leite FR, et al. Antigenic activity of bacterial endodontic contents
from primary root canal infection with periapical lesions against macrophage in the release of
interleukin-1b and tumor necrosis factor a. J Endod 2010;36:1467–74.

37. Martinho FC, Leite FR, Nascimento GG, et al. Clinical investigation of bacterial species and
endotoxin in endodontic infection and evaluation of root canal content activity against
macrophages by cytokine production. Clin Oral Investig 2014;18:2095–102.

38. Siqueira Jr JF. Rocas IN, Provenzano JC, Guilherme BP. Polymorphism of the FcgammaRIIIa
gene and post-treatment apical periodontitis. J Endod 2011;37:1345–8.
39. Stabholz A, McArthur WP. Cellular immune response of patients with periapical pathosis to
necrotic dental pulp antigens determined by release of LIF. J Endod 1978;4:282–7.

40. Takeichi O, Saito I, Okamoto Y, et al. Cytokine regulation on the synthesis of nitric oxide in vivo
by chronically infected human polymorphonuclear leucocytes. Immunology 1998;93:275–80.

41. Amaya MP, Criado L, Blanco B, et al. Polymorphisms of pro-inflammatory cytokine genes and
the risk for acute suppurative or chronic nonsuppurative apical periodontitis in a Colombian
population. Int Endod J 2013;46:71–8.

42. Evrosimovska B, Dimova C, Popovska L, Zabokova-Bilbilova E. Matrix matalloproteinase-8

gene polymorphism in chronic periapical lesions. Pril (Makedon Akad Nauk Umet Odd Med
Nauki) 2015;36:217–24.

43. Rocas IN, Siqueira Jr JF, Del Aguila CA, et al. Polymorphism of the CD14 and TLR4 genes and
post-treatment apical periodontitis. J Endod 2014;40:168–72.
44. Siqueira Jr JF, Rocas IN, Provenzano JC, et al. Relationship between Fcgamma receptor and
interleukin-1 gene polymorphisms and post-treatment apical periodontitis. J Endod
2009;35:1186–92.
45. Trombone AP, Cavalla F, Silveira EM, et al. MMP1-1607 polymorphism increases the risk for
periapical lesion development through the upregulation MMP-1 expression in association with
pro-inflammatory milieu elements. J Appl Oral Sci 2016;24:366–75.
46. Jakovljevic A, Andric M, Miletic M, et al. Epstein-Barr virus infection induces bone resorption in
apical periodontitis via increased production of reactive oxygen species. Med Hypotheses
2016;94:40–2.

1292 Georgiou et al. JOE  Volume 45, Number 11, November 2019
 47. Hackethal J, Gladbach-Stadt B, Lautenbach E. Blood protein and blood sedimentation studies
in odontogenic abscesses. II. ZWR 1979;88:1016–20.

48. Logan HL, Lutgendorf S, Kirchner HL, et al. Pain and immunologic response to root canal
treatment and subsequent health outcomes. Psychosom Med 2001;63:453–62.
49. Pessi T, Karhunen V, Karjalainen PP, et al. Bacterial signatures in thrombus aspirates of patients
with myocardial infarction. Circulation 2013;127:1219–28. e1–e6.
50. Torabinejad M, Theofilopoulos AN, Ketering JD, Bakland LK. Quantitation of circulating immune
complexes, immunoglobulins G and M, and C3 complement component in patients with large
periapical lesions. Oral Surg Oral Med Oral Pathol 1983;55:186–90.

51. Willershausen B, Kasaj A, Willershausen I, et al. Association between chronic dental infection
and acute myocardial infarction. J Endod 2009;35:626–30.

52. Willershausen I, Weyer V, Peter M, et al. Association between chronic periodontal and apical
inflammation and acute myocardial infarction. Odontology 2014;102:297–302.
53. Selle G. Genesis of jaw cysts based on comparative studies of cystic content and blood serum.
Dtsch Zahnarztl Z 1974;29:600–10.

54. Hackethal J, Lautenbach E. Serum protein and blood sedimentation studies in dentogenic
abscess. 1. ZWR 1979;88:912. 914–917.

55. Proctor ME, Turner DW, Kaminski EJ, et al. Determination and relationship of C-reactive protein
in human dental pulps and in serum. J Endod 1991;17:265–70.
56. Kettering JD, Torabinejad M. Concentrations of immune complexes, IgG, IgM, IgE, and C3 in
patients with acute apical abscesses. J Endod 1984;10:417–21.

57. Cotti E, Dessi C, Piras A, et al. Association of endodontic infection with detection of an initial
lesion to the cardiovascular system. J Endod 2011;37:1624–9.

58. Cotti E, Zedda A, Deidda M, et al. Endodontic infection and endothelial dysfunction are
associated with different mechanisms in men and women. J Endod 2015;41:594–600.
59. Marton I, Harmati S, Kiss C. Immunologic changes in patients with periapical granulomas. Z
Stomatol 1987;84:93–9.
60. Marton I, Kiss C, Balla G, et al. Acute phase proteins in patients with chronic periapical
granuloma before and after surgical treatment. Oral Microbiol Immunol 1988;3:95–6.

61. Marton IJ, Kiss C. Influence of surgical treatment of periapical lesions on serum and blood levels
of inflammatory mediators. Int Endod J 1992;25:229–33.
62. Inchingolo F, Marrelli M, Annibali S, et al. Influence of endodontic treatment on systemic oxidative
stress. Int J Med Sci 2014;11:1–6.
63. Jakimiak A, Kochan ska M, Michalska M, et al. Serum concentration of C-reactive protein in
patients treated for acute and chronic odontogenic infections. Dent Med Probl 2016;53:332–7.

64. Garrido M, Cardenas AM, Astorga J, et al. Elevated systemic inflammatory burden and
cardiovascular risk in young adults with endodontic apical lesions. J Endod 2019;45:111–5.
65. Gomes C, Martinho FC, Barbosa DS, et al. Increased root canal endotoxin levels are associated
with chronic apical periodontitis, increased oxidative and nitrosative stress, major depression,
severity of depression, and a lowered quality of life. Mol Neurobiol 2018;55:2814–27.
66. Harjunmaa U, Doyle R, Jarnstedt J, et al. Periapical infection may affect birth outcomes via
systemic inflammation. Oral Dis 2018;24:847–55.
67. Kimak A, Strycharz-Dudziak M, Bachanek T, Kimak E. Lipids and lipoproteins and inflammatory
markers in patients with chronic apical periodontitis. Lipids Health Dis 2015;14:162.

68. Sirin DA, Ozcelik F, Uzun C, et al. Association between C-reactive protein, neutrophil to
lymphocyte ratio and the burden of apical periodontitis: a case-control study. Acta Odontol
Scand 2019;77:142–9.

69. Abdolsamadi HR, Vahedi M, Esmaeili F, et al. Serum interleukin-6 as a serologic marker of
chronic periapical lesions: a case-control study. J Dent Res Dent Clin Dent Prospects
2008;2:43–7.

70. Anil S, Shanavas KR, Beena VT, et al. Quantitation of circulating immune complexes in patients
with chronic periapical lesions. J Nihon Univ Sch Dent 1993;35:175–8.
71. Boucher Jr NE, Hanrahan JJ, Kihara FY. Occurrence of C-reactive protein in oral disease. J Dent
Res 1967;46:624.

JOE  Volume 45, Number 11, November 2019 Apical Periodontitis and Inflammatory Mediators 1293
 72. Minczykowski A, Woszczyk M, Szczepanik A, et al. Hydrogen peroxide and superoxide anion
production by polymorphonuclear neutrophils in patients with chronic periapical granuloma,
before and after surgical treatment. Clin Oral Investig 2001;5:6–10.

73. Ren YF, Malmstrom HS. Rapid quantitative determination of C-reactive protein at chair side in
dental emergency patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104:49–
55.

74. van der Waal SV, Lappin DF, Crielaard W. Does apical periodontitis have systemic
consequences? The need for well-planned and carefully conducted clinical studies. Br Dent J
2015;218:513–6.

75. Wesselink PR. The incidental discovery of apical periodontitis. Endod Topics 2014;30:23–8.
76. Tjaderhane L. Endodontic infections and systemic health - where should we go? Int Endod J
2015;48:911–2.

77. McFadyen JD, Kiefer J, Braig D, et al. Dissociation of C-reactive protein localizes and amplifies
inflammation: Evidence for a direct biological role of C-reactive protein and its conformational
changes. Front Immunol 2018;9:1351.

78. Avan A, Tavakoly Sany SB, Ghayour-Mobarhan M, et al. Serum C-reactive protein in the
prediction of cardiovascular diseases: Overview of the latest clinical studies and public health
practice. J Cell Physiol 2018;233:8508–25.

79. Windgassen EB, Funtowicz L, Lunsford TN, et al. C-reactive protein and high-sensitivity C-
reactive protein: an update for clinicians. Postgrad Med 2011;123:114–9.

80. Bashashati M, Moradi M, Sarosiek I. Interleukin-6 in irritable bowel syndrome: a systematic

review and meta-analysis of IL-6 (-G174C) and circulating IL-6 levels. Cytokine 2017;99:132–8.
81. Simpson RJ, Hammacher A, Smith DK, et al. Interleukin-6: structure-function relationships.
Protein Sci 1997;6:929–55.

82. Hertle E, Stehouwer CD, van Greevenbroek MM. The complement system in human
cardiometabolic disease. Mol Immunol 2014;61:135–48.

83. Onat A, Hergenc G, Can G, et al. Serum complement C3: a determinant of cardiometabolic risk,
additive to the metabolic syndrome, in middle-aged population. Metabolism 2010;59:628–34.
84. Fukuchi M, Giaid A. Endothelial expression of endothelial nitric oxide synthase and endothelin-1
in human coronary artery disease. Specific reference to underlying lesion. Lab Invest
1999;79:659–70.
85. Kuvin JT, Ramet ME, Patel AR, et al. A novel mechanism for the beneficial vascular effects of
high-density lipoprotein cholesterol: enhanced vasorelaxation and increased endothelial nitric
oxide synthase expression. Am Heart J 2002;144:165–72.
86. van der Zwan LP, Scheffer PG, Dekker JM, et al. Systemic inflammation is linked to low arginine
and high ADMA plasma levels resulting in an unfavourable NOS substrate-to-inhibitor ratio: the
Hoorn Study. Clin Sci (Lond) 2011;121:71–8.

87. Schulze F, Lenzen H, Hanefeld C, et al. Asymmetric dimethylarginine is an independent risk

factor for coronary heart disease: results from the multicenter Coronary Artery Risk
Determination investigating the Influence of ADMA Concentration (CARDIAC) study. Am Heart J
2006;152:493.e1–8.
88. Palmieri B, Sblendorio V. Oxidative stress tests: overview on reliability and use. Part II. Eur Rev
Med Pharmacol Sci 2007;11:383–99.

89. Abramson JL, Hooper WC, Jones DP, et al. Association between novel oxidative stress
markers and C-reactive protein among adults without clinical coronary heart disease.
Atherosclerosis 2005;178:115–21.

90. Forman HJ, Bernardo A, Davies KJ. What is the concentration of hydrogen peroxide in blood
and plasma? Arch Biochem Biophys 2016;603:48–53.

91. Kessler RC, Aguilar-Gaxiola S, Alonso J, et al. The global burden of mental disorders: an update
from the WHO World Mental Health (WMH) surveys. Epidemiol Psichiatr Soc 2009;18:23–33.
92. World Health Organization. The global burden of disease. 2004. Available at: https://www.who.
int/healthinfo/global_burden_disease/2004_report_update/en/. Accessed May, 2 2019.

93. Halaris A, Myint AM, Savant V, et al. Does escitalopram reduce neurotoxicity in major
depression? J Psychiatr Res 2015;66-67:118–26.

94. Wiedlocha M, Marcinowicz P, Krupa R, et al. Effect of antidepressant treatment on peripheral

inflammation markers - a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry
2018;80(Pt C):217–26.

1294 Georgiou et al. JOE  Volume 45, Number 11, November 2019
 95. Madretsma GS, Donze GJ, van Dijk AP, et al. Nicotine inhibits the in vitro production of
interleukin 2 and tumour necrosis factor-alpha by human mononuclear cells.
Immunopharmacology 1996;35:47–51.

96. Kirkevang LL, Vaeth M, Horsted-Bindslev P, et al. Risk factors for developing apical periodontitis
in a general population. Int Endod J 2007;40:290–9.

97. Nile CJ, Apatzidou DA, Awang RA, et al. The effect of periodontal scaling and root polishing on
serum IL-17E concentrations and the IL-17A:IL-17E ratio. Clin Oral Investig 2016;20:2529–37.
98. Sartini C, Whincup PH, Wannamethee SG, et al. Associations of time of day with cardiovascular
disease risk factors measured in older men: results from the British Regional Heart Study. BMJ
Open 2017;7:e018264.
99. Tvedt TH, Rye KP, Reikvam H, et al. The importance of sample collection when using single
cytokine levels and systemic cytokine profiles as biomarkers–a comparative study of serum
versus plasma samples. J Immunol Methods 2015;418:19–28.
100. Bruserud O. Bidirectional crosstalk between platelets and monocytes initiated by Toll-like
receptor: an important step in the early defense against fungal infections? Platelets
2013;24:85–97.

JOE  Volume 45, Number 11, November 2019 Apical Periodontitis and Inflammatory Mediators 1295
SUPPLEMENTAL TABLE S1 - The Different Search Terms and Search Results

PubMed Session Results (February 4, 2019)

Number Query Results
#3 #1 AND #2 1,212
#2 ("Biomarkers"[Mesh] OR "Proteomics"[Mesh] OR "Proteome"[Mesh] OR biomarker*[tiab] OR marker*[tiab] OR 3,584,526
surrogate endpoint*[tiab] OR surrogate end point*[tiab] OR proteom*[tiab] OR polymorphonuclear neutrophil*
[tiab]) OR ("Inflammation Mediators"[Mesh] OR Mediators of Inflammation[tiab] OR Inflammation mediator*[tiab]
OR chemokine*[tiab] OR prostaglandin*[tiab]) OR ("Cytokines"[mesh] OR cytokine*[tiab] OR "autocrine motility
factor"[tiab] OR chemokine*[tiab] OR "beta thromboglobulin"[tiab] OR "beta 2 thromboglobulin"[tiab] OR
"monocyte chemotactic proteins"[tiab] OR interleukin*[tiab] OR "gamma thromboglobulin"[tiab] OR "heparin
neutralizing protein"[tiab] OR "heparin neutralizing proteins"[tiab] OR "antiheparin factor"[tiab] OR "macrophage
inflammatory protein"[tiab] OR "macrophage inflammatory proteins"[tiab] OR "prostate differentiation factor"[tiab]
OR "gdf 15"[tiab] OR "growth differentiation factor 15"[tiab] OR hematopoieti*[tiab] OR "colony stimulating
factor"[tiab] OR "colony stimulating factors"[tiab] OR "mgi 1"[tiab] OR "myeloid cell growth inducer"[tiab] OR
"macrophage granulocyte inducer"[tiab] OR "protein inducer mgi"[tiab] OR "recombinant g csf"[tiab] OR
"recombinant gm csf"[tiab] OR erythropoietin*[tiab] OR "growth and development factor"[tiab] OR "mgdf
factor"[tiab] OR thrombopoietin*[tiab] OR "myeloproliferative leukemia virus oncogene ligand"[tiab] OR
"thrombocytopoiesis stimulating factor"[tiab] OR thrombocytopoietin*[tiab] OR "mpl ligand"[tiab] OR "stem cell
factor"[tiab] OR "steel factor"[tiab] OR "mast cell growth factor"[tiab] OR "kit ligand"[tiab] OR "hepatocyte growth
factor"[tiab] OR "scatter factor"[tiab] OR hepatopoietin*[tiab] OR interferon*[tiab] OR il1[tiab] OR "il 1"[tiab] OR "il
1ra"[tiab] OR "t helper factor"[tiab] OR "lymphocyte activating factor"[tiab] OR "macrophage cell factor"[tiab] OR
"epidermal cell derived thymocyte activating factor"[tiab] OR catabolin*[tiab] OR il10[tiab] OR "il 10"[tiab] OR "csif
10"[tiab] OR il11[tiab] OR "il 11"[tiab] OR "adipogenesis inhibitory factor"[tiab] OR "il 12"[tiab] OR il12[tiab] OR
"natural killer cell stimulatory factor"[tiab] OR "il 12p35"[tiab] OR "il 12p40"[tiab] OR il13[tiab] OR "il 13"[tiab] OR il15
[tiab] OR "il 15"[tiab] OR il16[tiab] OR "il 16"[tiab] OR "lymphocyte chemoattractant factor"[tiab] OR "lcf factor"[tiab]
OR il17[tiab] OR "il 17"[tiab] OR "ctla 8"[tiab] OR ctla8[tiab] OR il17b[tiab] OR "il 17b"[tiab] OR il17f[tiab] OR "il
17f"[tiab] OR il17e[tiab] OR "il 17e"[tiab] OR il17a[tiab] OR "il 17a"[tiab] OR il17c[tiab] OR "il 17c"[tiab] OR "cytotoxic
t lymphocyte associated antigen"[tiab] OR il17d[tiab] OR "il 17d"[tiab] OR il18[tiab] OR "il 18"[tiab] OR "ifn gamma
inducing factor"[tiab] OR "interferon gamma inducing factor"[tiab] OR tcgf[tiab] OR "lymphocyte mitogenic
factor"[tiab] OR "t cell growth factor"[tiab] OR "t cell stimulating factor"[tiab] OR "thymocyte stimulating factor"[tiab]
OR "ro 23 6019"[tiab] OR ro236019[tiab] OR "ro 236019"[tiab] OR "ru 49637"[tiab] OR ru49637[tiab] OR il23[tiab]
OR "il 23"[tiab] OR "il 23p19"[tiab] OR "il 23 p19"[tiab] OR "p cell stimulating factor"[tiab] OR "erythrocyte burst
promoting factor"[tiab] OR il3[tiab] OR "il 3"[tiab] OR "b cell growth factor"[tiab] OR "b cell proliferating factor"[tiab]
OR "b cell stimulating factor"[tiab] OR "b cell stimulatory factor"[tiab] OR bcgf[tiab] OR il4[tiab] OR "il 4"[tiab] OR
"bsf 1"[tiab] OR "mcgf 2"[tiab] OR il5[tiab] OR "il 5"[tiab] OR "t cell replacing factor"[tiab] OR "eosinophil
differentiation factor"[tiab] OR il6[tiab] OR "il 6"[tiab] OR "plasmacytoma growth factor"[tiab] OR "bsf 2"[tiab] OR "b
cell differentiation factor"[tiab] OR "hepatocyte stimulating factor"[tiab] OR "hybridoma growth factor"[tiab] OR "ifn
beta 2"[tiab] OR "mgi 2"[tiab] OR "myeloid differentiation inducing protein"[tiab] OR il7[tiab] OR "il 7"[tiab] OR
"lymphopoietin 1"[tiab] OR "il 8"[tiab] OR il8[tiab] OR "chemotactic factor"[tiab] OR "neutrophil activation
factor"[tiab] OR "neutrophil activating peptide"[tiab] OR cxcl8[tiab] OR "chemotactic factor"[tiab] OR "chemotactic
peptide"[tiab] OR "amcf i"[tiab] OR "il 9"[tiab] OR il9[tiab] OR Transforming Growth Factor*[tiab] OR TGFbeta[tiab]
OR TGF-beta[tiab] OR Tumor Necrosis Factor*[tiab] OR TNF[tiab] OR rank[tiab] OR rankl[tiab] OR srankl[tiab]) OR
("Immunoproteins"[Mesh] OR Immunoprotein*[tiab] OR c-reactive protein*[tiab] OR CRP[tiab] OR
immunoglobulin*[tiab] OR immuno-globulin*[tiab]) OR ("Endopeptidases"[Mesh] OR Endopeptidas*[tiab]) OR
("Osteocalcin"[Mesh] OR Osteocalcin[tiab] OR osteoimmunolog*[tiab] OR osteo-immunolog*[tiab] OR bone gla
[tiab]) OR ("collagen type I trimeric cross-linked peptide"[Supplementary Concept] OR ICTP[tiab]) OR
("Prostaglandin-Endoperoxide Synthases"[Mesh] OR Prostaglandin Endoperoxide Synthas*[tiab] OR Arachidonic
Acid[tiab] OR Cyclooxygenase[tiab] OR Cyclo-oxygenase[tiab]) OR ("Acute-Phase Proteins"[Mesh] OR Acute-
Phase Protein*[tiab] OR Serum Amyloid[tiab] OR Amyloid A[tiab] OR Amyloid Protein*[tiab]) OR ("Protein
Degradation End Products"[Mesh] OR Protein Degradation[tiab])
#1 "Periapical Diseases"[Mesh] OR "Dental Pulp Diseases"[Mesh:NoExp] OR "Dental Pulp Necrosis"[Mesh] OR "Tooth, 17,644
Nonvital"[Mesh] OR "Periapical Tissue"[Mesh] OR "Tooth Apex"[Mesh] OR Periapical Disease*[tiab] OR Periapical
Periodontit*[tiab] OR Apical Periodontit*[tiab] OR Periapical Abscess*[tiab] OR Apical Abscess*[tiab] OR Periapical
granuloma*[tiab] OR Apical granuloma*[tiab] OR Radicular Cyst*[tiab] OR Periapical Cyst*[tiab] OR Apical Cyst*
[tiab] OR Pulp Necros*[tiab] OR Pulp Gangrene*[tiab] OR Pulp Mummification*[tiab] OR ((Nonvital[tiab] OR Non-
vital[tiab] OR Devitalized[tiab] OR Devitalised[tiab] OR Pulpless[tiab]) AND (tooth[tiab] OR teeth[tiab])) OR ((apical
[tiab] OR periapical[tiab] OR radicular[tiab] OR periradicular[tiab]) AND (lesion[tiab] OR lesions[tiab]) AND (dental
[tiab] OR endodont*[tiab] OR periodont*[tiab]))

[Mesh], Medical Subject Headings; [Mesh:NoExp], Medical Subject Headings without explosion; [tiab], words in title or abstract or author key words.

1295.e1 Georgiou et al. JOE  Volume 45, Number 11, November 2019
 Embase.com Session Results (4 February 2019)
Number Query Results
#3 #1 AND #2 1,352
#2 ’marker’/exp OR ’proteomics’/exp OR ’proteome’/exp OR biomarker*:ab,ti,kw OR marker*:ab,ti,kw OR ’surrogate 5,243,456
endpoint*’:ab,ti,kw OR ’surrogate end point*’:ab,ti,kw OR proteom*:ab,ti,kw OR ’polymorphonuclear
neutrophil*’:ab,ti,kw OR ’biological factor’/exp OR ((inflammation NEAR/3 mediator*):ab,ti,kw) OR
prostaglandin*:ab,ti,kw OR cytokine*:ab,ti,kw OR ’autocrine motility factor’:ab,ti,kw OR chemokine*:ab,ti,kw OR
’beta thromboglobulin’:ab,ti,kw OR ’beta 2 thromboglobulin’:ab,ti,kw OR ’monocyte chemotactic
proteins’:ab,ti,kw OR interleukin*:ab,ti,kw OR ’gamma thromboglobulin’:ab,ti,kw OR ’heparin neutralizing
protein’:ab,ti,kw OR ’heparin neutralizing proteins’:ab,ti,kw OR ’antiheparin factor’:ab,ti,kw OR ’macrophage
inflammatory protein’:ab,ti,kw OR ’macrophage inflammatory proteins’:ab,ti,kw OR ’prostate differentiation
factor’:ab,ti,kw OR ’gdf 15’:ab,ti,kw OR ’growth differentiation factor 15’:ab,ti,kw OR hematopoieti*:ab,ti,kw OR
’colony stimulating factor’:ab,ti,kw OR ’colony stimulating factors’:ab,ti,kw OR ’mgi 1’:ab,ti,kw OR ’myeloid cell
growth inducer’:ab,ti,kw OR ’macrophage granulocyte inducer’:ab,ti,kw OR ’protein inducer mgi’:ab,ti,kw OR
’recombinant g csf’:ab,ti,kw OR ’recombinant gm csf’:ab,ti,kw OR erythropoietin*:ab,ti,kw OR ’growth and
development factor’:ab,ti,kw OR ’mgdf factor’:ab,ti,kw OR thrombopoietin*:ab,ti,kw OR ’myeloproliferative
leukemia virus oncogene ligand’:ab,ti,kw OR ’thrombocytopoiesis stimulating factor’:ab,ti,kw OR
thrombocytopoietin*:ab,ti,kw OR ’mpl ligand’:ab,ti,kw OR ’stem cell factor’:ab,ti,kw OR ’steel factor’:ab,ti,kw OR
’mast cell growth factor’:ab,ti,kw OR ’kit ligand’:ab,ti,kw OR ’hepatocyte growth factor’:ab,ti,kw OR ’scatter
factor’:ab,ti,kw OR hepatopoietin*:ab,ti,kw OR interferon*:ab,ti,kw OR il1:ab,ti,kw OR ’il 1’:ab,ti,kw OR ’il
1ra’:ab,ti,kw OR ’t helper factor’:ab,ti,kw OR ’lymphocyte activating factor’:ab,ti,kw OR ’macrophage cell
factor’:ab,ti,kw OR ’epidermal cell derived thymocyte activating factor’:ab,ti,kw OR catabolin*:ab,ti,kw OR
il10:ab,ti,kw OR ’il 10’:ab,ti,kw OR ’csif 10’:ab,ti,kw OR il11:ab,ti,kw OR ’il 11’:ab,ti,kw OR ’adipogenesis
inhibitory factor’:ab,ti,kw OR ’il 12’:ab,ti,kw OR il12:ab,ti,kw OR ’natural killer cell stimulatory factor’:ab,ti,kw OR ’il
12p35’:ab,ti,kw OR ’il 12p40’:ab,ti,kw OR il13:ab,ti,kw OR ’il 13’:ab,ti,kw OR il15:ab,ti,kw OR ’il 15’:ab,ti,kw OR
il16:ab,ti,kw OR ’il 16’:ab,ti,kw OR ’lymphocyte chemoattractant factor’:ab,ti,kw OR ’lcf factor’:ab,ti,kw OR
il17:ab,ti,kw OR ’il 17’:ab,ti,kw OR ’ctla 8’:ab,ti,kw OR ctla8:ab,ti,kw OR il17b:ab,ti,kw OR ’il 17b’:ab,ti,kw OR
il17f:ab,ti,kw OR ’il 17f’:ab,ti,kw OR il17e:ab,ti,kw OR ’il 17e’:ab,ti,kw OR il17a:ab,ti,kw OR ’il 17a’:ab,ti,kw OR
il17c:ab,ti,kw OR ’il 17c’:ab,ti,kw OR ’cytotoxic t lymphocyte associated antigen’:ab,ti,kw OR il17d:ab,ti,kw OR ’il
17d’:ab,ti,kw OR il18:ab,ti,kw OR ’il 18’:ab,ti,kw OR ’ifn gamma inducing factor’:ab,ti,kw OR ’interferon gamma
inducing factor’:ab,ti,kw OR tcgf:ab,ti,kw OR ’lymphocyte mitogenic factor’:ab,ti,kw OR ’t cell growth
factor’:ab,ti,kw OR ’t cell stimulating factor’:ab,ti,kw OR ’thymocyte stimulating factor’:ab,ti,kw OR ’ro 23
6019’:ab,ti,kw OR ro236019:ab,ti,kw OR ’ro 236019’:ab,ti,kw OR ’ru 49637’:ab,ti,kw OR ru49637:ab,ti,kw OR
il23:ab,ti,kw OR ’il 23’:ab,ti,kw OR ’il 23p19’:ab,ti,kw OR ’il 23 p19’:ab,ti,kw OR ’p cell stimulating factor’:ab,ti,kw
OR ’erythrocyte burst promoting factor’:ab,ti,kw OR il3:ab,ti,kw OR ’il 3’:ab,ti,kw OR ’b cell growth factor’:ab,ti,kw
OR ’b cell proliferating factor’:ab,ti,kw OR ’b cell stimulating factor’:ab,ti,kw OR ’b cell stimulatory factor’:ab,ti,kw
OR bcgf:ab,ti,kw OR il4:ab,ti,kw OR ’il 4’:ab,ti,kw OR ’bsf 1’:ab,ti,kw OR ’mcgf 2’:ab,ti,kw OR il5:ab,ti,kw OR ’il
5’:ab,ti,kw OR ’t cell replacing factor’:ab,ti,kw OR ’eosinophil differentiation factor’:ab,ti,kw OR il6:ab,ti,kw OR ’il
6’:ab,ti,kw OR ’plasmacytoma growth factor’:ab,ti,kw OR ’bsf 2’:ab,ti,kw OR ’b cell differentiation factor’:ab,ti,kw
OR ’hepatocyte stimulating factor’:ab,ti,kw OR ’hybridoma growth factor’:ab,ti,kw OR ’ifn beta 2’:ab,ti,kw OR
’mgi 2’:ab,ti,kw OR ’myeloid differentiation inducing protein’:ab,ti,kw OR il7:ab,ti,kw OR ’il 7’:ab,ti,kw OR
’lymphopoietin 1’:ab,ti,kw OR ’il 8’:ab,ti,kw OR il8:ab,ti,kw OR ’neutrophil activation factor’:ab,ti,kw OR
’neutrophil activating peptide’:ab,ti,kw OR cxcl8:ab,ti,kw OR ’chemotactic factor’:ab,ti,kw OR ’chemotactic
peptide’:ab,ti,kw OR ’amcf i’:ab,ti,kw OR ’il 9’:ab,ti,kw OR il9:ab,ti,kw OR ’transforming growth factor*’:ab,ti,kw
OR tgfbeta:ab,ti,kw OR ’tgf-beta’:ab,ti,kw OR ’tumor necrosis factor*’:ab,ti,kw OR tnf:ab,ti,kw OR rank:ab,ti,kw
OR rankl:ab,ti,kw OR srankl:ab,ti,kw OR ’plasma protein’/de OR ’c reactive protein’/exp OR ’eosinophil granule
protein’/exp OR ’immunoglobulin’/exp OR ’proteinase’/exp OR ’osteocalcin’/exp OR ’prostaglandin synthase’/
exp OR ’acute phase protein’/exp OR ’protein degradation end product’/exp OR immunoprotein*:ab,ti,kw OR ’c-
reactive protein*’:ab,ti,kw OR crp:ab,ti,kw OR immunoglobulin*:ab,ti,kw OR ’immuno-globulin*’:ab,ti,kw OR
endopeptidas*:ab,ti,kw OR osteocalcin:ab,ti,kw OR osteoimmunolog*:ab,ti,kw OR ’osteo-immunolog*’:ab,ti,kw
OR ’bone gla’:ab,ti,kw OR ictp:ab,ti,kw OR ’prostaglandin endoperoxide synthas*’:ab,ti,kw OR ’arachidonic
acid’:ab,ti,kw OR cyclooxygenase:ab,ti,kw OR ’cyclo-oxygenase’:ab,ti,kw OR ’acute-phase protein*’:ab,ti,kw
OR ’serum amyloid’:ab,ti,kw OR ’amyloid a’:ab,ti,kw OR ’amyloid protein*’:ab,ti,kw OR ’protein
degradation’:ab,ti,kw
#1 ’tooth periapical disease’/exp OR ’tooth pulp disease’/exp OR ’periapical tissue’/exp OR ’tooth apex’/exp OR 16,277
’Periapical Disease*’:ab,ti,kw OR ’Periapical Periodontit*’:ab,ti,kw OR ’Apical Periodontit*’:ab,ti,kw OR ’Periapical
Abscess*’:ab,ti,kw OR ’Apical Abscess*’:ab,ti,kw OR ’Periapical granuloma*’:ab,ti,kw OR ’Apical
granuloma*’:ab,ti,kw OR ’Radicular Cyst*’:ab,ti,kw OR ’Periapical Cyst*’:ab,ti,kw OR ’Apical Cyst*’:ab,ti,kw OR
’Pulp Necros*’:ab,ti,kw OR ’Pulp Gangrene*’:ab,ti,kw OR ’Pulp Mummification*’:ab,ti,kw OR ((Nonvital:ab,ti,kw
OR ’Non-vital’:ab,ti,kw OR Devitalized:ab,ti,kw OR Devitalised:ab,ti,kw OR Pulpless:ab,ti,kw) AND (tooth:ab,ti,kw
OR teeth:ab,ti,kw)) OR ((apical:ab,ti,kw OR periapical:ab,ti,kw OR radicular:ab,ti,kw OR periradicular:ab,ti,kw)
AND (lesion:ab,ti,kw OR lesions:ab,ti,kw) AND (dental:ab,ti,kw OR endodont*:ab,ti,kw OR periodont*:ab,ti,kw))

/exp, EMtree keyword with explosion; /de, EMtree keyword without explosion; :ab,ti,kw, words in title or abstract or author keywords.

JOE  Volume 45, Number 11, November 2019 Apical Periodontitis and Inflammatory Mediators 1295.e2
 Wiley / Cochrane Library Session Results (4 February 2019)
Number Query Results
#3 #1 AND #2 30
#2 (biomarker* OR marker* OR "surrogate endpoint*" OR "surrogate end point*" OR proteom* OR "polymorphonuclear 138,649
neutrophil*" OR (inflammation NEAR/3 mediator*) OR prostaglandin* OR cytokine* OR "autocrine motility factor" OR
chemokine* OR "beta thromboglobulin" OR "beta 2 thromboglobulin" OR "monocyte chemotactic proteins" OR
interleukin* OR "gamma thromboglobulin" OR "heparin neutralizing protein" OR "heparin neutralizing proteins" OR
"antiheparin factor" OR "macrophage inflammatory protein" OR "macrophage inflammatory proteins" OR "prostate
differentiation factor" OR "gdf 15" OR "growth differentiation factor 15" OR hematopoieti* OR "colony stimulating
factor" OR "colony stimulating factors" OR "mgi 1" OR "myeloid cell growth inducer" OR "macrophage granulocyte
inducer" OR "protein inducer mgi" OR "recombinant g csf" OR "recombinant gm csf" OR erythropoietin* OR "growth
and development factor" OR "mgdf factor" OR thrombopoietin* OR "myeloproliferative leukemia virus oncogene
ligand" OR "thrombocytopoiesis stimulating factor" OR thrombocytopoietin* OR "mpl ligand" OR "stem cell factor" OR
"steel factor" OR "mast cell growth factor" OR "kit ligand" OR "hepatocyte growth factor" OR "scatter factor" OR
hepatopoietin* OR interferon* OR il1 OR "il 1" OR "il 1ra" OR "t helper factor" OR "lymphocyte activating factor" OR
"macrophage cell factor" OR "epidermal cell derived thymocyte activating factor" OR catabolin* OR il10 OR "il 10" OR
"csif 10" OR il11 OR "il 11" OR "adipogenesis inhibitory factor" OR "il 12" OR il12 OR "natural killer cell stimulatory
factor" OR "il 12p35" OR "il 12p40" OR il13 OR "il 13" OR il15 OR "il 15" OR il16 OR "il 16" OR "lymphocyte
chemoattractant factor" OR "lcf factor" OR il17 OR "il 17" OR "ctla 8" OR ctla8 OR il17b OR "il 17b" OR il17f OR "il 17f"
OR il17e OR "il 17e" OR il17a OR "il 17a" OR il17c OR "il 17c" OR "cytotoxic t lymphocyte associated antigen" OR
il17d OR "il 17d" OR il18 OR "il 18" OR "ifn gamma inducing factor" OR "interferon gamma inducing factor" OR tcgf OR
"lymphocyte mitogenic factor" OR "t cell growth factor" OR "t cell stimulating factor" OR "thymocyte stimulating factor"
OR "ro 23 6019" OR ro236019 OR "ro 236019" OR "ru 49637" OR ru49637 OR il23 OR "il 23" OR "il 23p19" OR "il 23
p19" OR "p cell stimulating factor" OR "erythrocyte burst promoting factor" OR il3 OR "il 3" OR "b cell growth factor"
OR "b cell proliferating factor" OR "b cell stimulating factor" OR "b cell stimulatory factor" OR bcgf OR il4 OR "il 4" OR
"bsf 1" OR "mcgf 2" OR il5 OR "il 5" OR "t cell replacing factor" OR "eosinophil differentiation factor" OR il6 OR "il 6" OR
"plasmacytoma growth factor" OR "bsf 2" OR "b cell differentiation factor" OR "hepatocyte stimulating factor" OR
"hybridoma growth factor" OR "ifn beta 2" OR "mgi 2" OR "myeloid differentiation inducing protein" OR il7 OR "il 7" OR
"lymphopoietin 1" OR "il 8" OR il8 OR "neutrophil activation factor" OR "neutrophil activating peptide" OR cxcl8 OR
"chemotactic factor" OR "chemotactic peptide" OR "amcf i" OR "il 9" OR il9 OR "transforming growth factor*" OR
tgfbeta OR "tgf-beta" OR "tumor necrosis factor*" OR tnf OR rank OR rankl OR srankl OR immunoprotein* OR "c-
reactive protein*" OR crp OR immunoglobulin* OR "immuno-globulin*" OR endopeptidas* OR osteocalcin OR
osteoimmunolog* OR "osteo-immunolog*" OR "bone gla" OR ictp OR "prostaglandin endoperoxide synthas*" OR
"arachidonic acid" OR cyclooxygenase OR "cyclo-oxygenase" OR "acute-phase protein*" OR "serum amyloid" OR
"amyloid a" OR "amyloid protein*" OR "protein degradation"):ab,ti,kw
#1 ("Periapical Disease*" OR "Periapical Periodontit*" OR "Apical Periodontit*" OR "Periapical Abscess*" OR "Apical 802
Abscess*" OR "Periapical granuloma*" OR "Apical granuloma*" OR "Radicular Cyst*" OR "Periapical Cyst*" OR
"Apical Cyst*" OR "Pulp Necros*" OR "Pulp Gangrene*" OR "Pulp Mummification*" OR ((Nonvital OR "Non-vital" OR
Devitalized OR Devitalised OR Pulpless) AND (tooth OR teeth)) OR ((apical OR periapical OR radicular OR
periradicular) AND (lesion OR lesions) AND (dental OR endodont* OR periodont*))):ab,ti,kw

:ab,ti,kw, words in title or abstract or author keywords.

1295.e3 Georgiou et al. JOE  Volume 45, Number 11, November 2019