Accepted: 3 February 2018

DOI: 10.1111/jre.12543

ORIGINAL ARTICLE

Increased systemic levels of inflammatory mediators following

one-stage full-­mouth scaling and root planing

T. Morozumi1  | A. Yashima2 | K. Gomi2 | Y. Ujiie2 | Y. Izumi3 | T. Akizuki3 | 

K. Mizutani3 | H. Takamatsu3 | M. Minabe4,5 | S. Miyauchi4 | T. Yoshino6 | 
M. Tanaka6 | Y. Tanaka6 | T. Hokari1 | H. Yoshie1

1
Division of Periodontology, Department of
Oral Biological Science, Niigata University Background and Objective: Full-­mouth scaling and root planing (FM-­SRP) acts as a
Graduate School of Medical and Dental potent inflammatory stimulus immediately after treatment; however, systemic
Sciences, Niigata, Japan
2
­inflammation typically improves in the long term. The contribution of FM-­SRP to
Department of Periodontology, School
of Dental Medicine, Tsurumi University, systemic biological and acute-­phase responses is largely unknown. The purpose of
Yokohama, Japan this prospective intervention study was to assess the systemic and local biological
3
Department of Periodontology, Graduate
responses after FM-­SRP.
School of Medical and Dental
Sciences, Tokyo Medical and Dental Material and Methods: Thirty-­one patients with generalized moderate-­to-­severe
University, Tokyo, Japan
chronic periodontitis received 1-­stage FM-­SRP. Measurement of clinical parameters
4
Bunkyo-Dori Dental Clinic, Chiba, Japan
5
and body temperature as well as collection of subgingival plaque, peripheral blood
Division of Periodontology, Department
of Oral Interdisciplinary Medicine, School and gingival crevicular fluid was performed before and after treatment 2 or 3 times.
of Dentistry, Kanagawa Dental University, Quantification of periodontopathic bacteria in the sulcus and measurement of cor-
Yokosuka, Japan
6
responding serum IgG titers were performed. Systemic and local inflammatory mark-
Seikeikai Hospital, Seikeikai Group,
Yokohama, Japan ers such as endotoxin, high-­sensitive C-­reactive protein (hs-­CRP) and 6 inflammatory
cytokines were assessed using high-­sensitivity assays.
Correspondence
Toshiya Morozumi, Division of Results: Compared to baseline values, FM-­SRP resulted in a substantial improvement
Periodontology, Department of Oral
in clinical parameters (P < .05), lower bacterial counts (P < .01) and a significant de-
Biological Science, Niigata University
Graduate School of Medical and Dental crease of IgG titers against Porphyromonas gingivalis (P < .001) 6 weeks after treat-
Sciences, Niigata, Japan.
ment. Comparing baseline parameters to those at 1 day post-­treatment, there was a
Email: moro@dent.niigata-u.ac.jp
statistically significant elevation in body temperature (P = .007). In addition, a 5-­fold
Funding information
This study was supported by research funds increase in hs-­CRP (P < .001), a remarkable increase in interferon-­γ (P < .001) and a
from Pfizer Inc., New York, NY, USA. slight increase in interleukin (IL)-­12p70 (P = .001) were detected in serum samples. In
the gingival crevicular fluid, marked increases in hs-­CRP (P < .001), IL-­5 (P = .001), IL-­
6, IL-­12p70 and tumor necrosis factor-­α (P < .001 for the latter 3 markers) were noted
1 day after treatment. Endotoxin levels were below measurable limits for most time
points.
Conclusions: FM-­SRP resulted in clinical and microbiological improvement 6 weeks
post-­treatment, but produced a moderate systemic acute-­phase response including
elevated inflammatory mediators 1 day post-­treatment.

KEYWORDS
acute-phase reaction, full-mouth scaling and root planing, inflammatory mediators, serum

T. Morozumi and A. Yashima contributed equally to this work.

J Periodont Res. 2018;1–9. wileyonlinelibrary.com/journal/jre   © 2018 John Wiley & Sons A/S. |  1
Published by John Wiley & Sons Ltd
 |
2       MOROZUMI et al.
1 |  I NTRO D U C TI O N
Accumulating evidence suggests that periodontal infection is as-
sociated with an increased risk of a variety of diseases such as
atherosclerotic vascular disease and type 2 diabetes.1,2 The basis
for this association could be the release of bacterial products and
inflammatory mediators from periodontal pockets into the blood-
stream, resulting in low-­grade systemic inflammation and con-
tributing to the development of these systemic diseases. 3 Serum
high sensitivity C-­reactive protein (hs-­CRP) and interleukin (IL)-­6
are known as important markers of systemic inflammation. 3-5
Proinflammatory (eg, tumor necrosis factor-­α [TNF-­α], interferon
[IFN-­γ] and IL-­12) markers have been also identified in serum or
gingival crevicular fluid because of cellular responses around peri-
odontal tissues. 6,7
Scaling and root planing (SRP) is an essential procedure for
treating periodontitis, and is frequently performed during the ini-
tial phase of periodontal treatment to remove its etiologic agents.
Full-­mouth SRP (FM-­SRP) is known as a current alternative mechan-
ical treatment option for generalized chronic periodontitis.8,9 This
treatment, which does not involve the adjunct use of antiseptics or
antimicrobial agents, is performed within 24 hours, and can miti-
gate bacterial reinfection from untreated periodontal pockets to the
treated sites.10,11 In addition, the use of this procedure could reduce
the treatment period, sessions and cost.8,9
Although SRP improves systemic inflammation in the long term,
intense non-­surgical periodontal therapy including FM-­SRP acts as
a potent inflammatory stimulus immediately after treatment, and in-
duces an acute inflammatory response.12,13 Recently, Graziani et al14
reported that FM-­SRP results in a strong systemic acute-­phase re-
sponse that includes CRP and IL-­6 , after 24 hours in patients with
periodontitis. It is thus a concern that the marked systemic spread
of inflammatory mediators from periodontal pockets and tissues
following FM-­SRP might cause transient hypercytokinemia.
Most previous studies in this field have mainly focused on the
clinical and microbiological effects of FM-­SRP;11,15,16 knowledge of
the contribution of FM-­SRP to the systemic biological response is
limited. In addition, little information is available regarding the sys-
temic acute-­phase response including fever and the production of
inflammatory mediators after FM-­SRP.12,14 Furthermore, as far as we
are aware, no study has concurrently evaluated changes in serum
and gingival crevicular fluid inflammatory markers. In summary, the
systemic influence of FM-­SRP has not been fully elucidated, and
thus is worth investigating.
Considering all these aspects, one might hypothesize that
the systemic acute-­p hase response including elevated inflamma-
tory mediators and body temperature might occur following FM-­
SRP. The objectives of this study were to investigate the effects
of FM-­S RP on clinical and microbiological markers, systemic and
local levels of CRP, and inflammatory cytokines in patients with
generalized chronic periodontitis, in addition to clarifying the sys-
temic influence of FM-­S RP on acute-­p hase responses following
treatment.
2 | M ATE R I A L A N D M E TH O DS
2.1 | Subjects
This study was a multicenter prospective intervention trial with a 6-­week
follow-­up. Thirty-­one patients diagnosed with generalized moderate-­
to-­severe chronic periodontitis, according to criteria of the Guidelines
of the American Academy of Periodontology (moderate: 3-­4 mm clini-
cal attachment loss, severe: ≥5 mm loss, generalized: >30% of sites af-
fected),17 were recruited from 5 facilities (3 university hospitals and 2
clinics) in Japan, between June 2012 and August 2015. The protocol
was approved by the Institutional Review Board of each participating
institution, and was registered within a clinical trials database (UMIN-­
CTR, No. UMIN000008411). Informed written consent was obtained
from each subject before participation in the study. All individuals were
≥30 years of age, systemically healthy, non-­smokers and possessed at
least 20 teeth. Subjects with the following conditions were excluded:
congenital valve defects or any other situation that increases the risk
for infectious endocarditis, low levels of hematocrit and/or hemoglobin,
high risk of cardiovascular disease and diabetes, and patients who had
taken systemic antibiotics, anti-­inflammatory drugs or immunosuppres-
sive drugs within 3 months of enrollment. Subjects, who had received
periodontal treatment within the previous 6 months, regularly used an
oral irrigation device and/or mouth rinse, and had an incompatible den-
tition such as orthodontic bands, partial dentures or teeth unsuitable for
extensive ultrasonic scaling, were also excluded.
2.2 | Clinical protocol
The study flowchart is shown in Figure 1. For greater than 1 month
before the study, all subjects received standard oral hygiene instruc-
tions over the course of several visits, full-­mouth supragingival scal-
ing and achieved effective individual plaque control, and specifically,
a plaque control record <20%.18 For baseline parameters, sample
collection including peripheral blood, gingival crevicular fluid and
subgingival plaque, in addition to periodontal examination was per-
formed. After 1 week, 1-­stage FM-­SRP was performed using both
hand and ultrasonic instrumentation with fine tips under local anes-
thesia with 2% lidocaine (plus 1:80 000 epinephrine) in a single visit,
and was completed within ~2 hours. The second set of peripheral
blood and gingival crevicular fluid samples was taken 1 day after
treatment. Subsequently, all sampling and periodontal examinations
were performed 6 weeks after FM-­SRP. Body temperature in the
morning was measured 3 times: before 3 days, on the day of the pro-
cedure, and 1 day after FM-­SRP. Patients used a digital thermometer
(Omron Electronic Thermometer MC-­674, OMRON HEALTHCARE
Co., Ltd., Kyoto, Japan) according to the manufacturer’s instructions
and recorded the temperature on a chart.
2.3 | Clinical assessment
The following clinical parameters were recorded based on periodon-
tal examination: plaque index (PlI),19 gingival index (GI), 20 bleeding
on probing (BOP), 21 probing depth22 and clinical attachment level. 23
MOROZUMI et al.
PlI and GI were recorded at 4 sites per tooth (mesial, buccal, dis-
tal and lingual). BOP, probing depth and clinical attachment level
were recorded at 6 sites per tooth (mesiobuccal, buccal, distobuccal,
mesiolingual, lingual and distolingual). Rate of bone resorption was
calculated based on the alveolar bone-­defect depth measured using
dental X-­ray radiographs. These data were used for the diagnosis of
periodontitis and secondary endpoint. The calibration of 5 examin-
ers who are periodontists, was carried out using 2 different types
of periodontal disease models (P15FE-­500HPRO-­S2A1-­GSF, P15FE-­
500HPRO-­
S2A1-­
GSD; NISSIN, Kyoto, Japan) before the start of
the study. Full-­mouth probing depth and recessions were measured
twice, the intra-­examiner repeatability for clinical attachment level
was assessed. The examiner was judged reproducible after reaching
a percentage of agreement within ±1 mm between repeated meas-
urements of at least 95%.
2.4 | Sample collection
The 2 deepest periodontal pockets were selected as the sites for
sampling of subgingival plaque and gingival crevicular fluid. The
sites to be sampled were isolated with cotton rolls and dried with
a gentle stream of air to prevent contamination by saliva. After re-
moving the supragingival plaque, a subgingival plaque sample was
taken by inserting 2 sterile no. 40 paper points (Zipperer Absorbent
Paper Points, VDW GmbH, Munich, Germany) consecutively into
the periodontal pocket for 10 seconds. For gingival crevicular fluid
collection, a sterile Perio-­paper strip (Harco Electronics, Winnipeg,
MB, Canada) was gently inserted into the orifice of the gingival
crevice, until mild resistance was felt, and was then left in place for
Periodontal examination
Enrollment of subjects from patients with generalized
moderate-to-severe chronic periodontitis (n = 31)
Sampling of peripheral blood, GCF (from 1 deep site),
and subgingival plaque (from another deep site)
Periodontal examination (n = 29)
Measurement of body temperature (n = 29)
Measurement of body temperature (n = 29)
Measurement of body temperature
Sampling of peripheral blood and GCF (n = 28)
Sampling of peripheral blood, GCF, and subgingival plaque
Periodontal examination (n = 28)
F I G U R E   1   Flowchart of the study from enrollment to completion of the trial. GCF, gingival crevicular fluid; SRP, scaling and root planing
|
      3
30 seconds. This gingival crevicular fluid sampling was consecutively
repeated 4 times. Gingival crevicular fluid samples were placed in
tubes with transport medium containing 200 μL of phosphate-­
buffered saline without calcium chloride or magnesium chloride,
supplemented with 0.5% bovine serum albumin. After shaking for
15 minutes, the eluates were centrifuged for 10 minutes at 12 000 g
to remove plaque and cellular elements and the strips were re-
moved. The samples were frozen at −80°C until further analysis.
Peripheral blood samples were obtained by venipuncture in the
antecubital fossa. Before sampling, the skin overlying the vein was
swabbed with ethyl alcohol and then chlorhexidine to minimize the
number of potential skin contaminants. Each sample consisted of
12 mL of blood, which was obtained using a 23-­gauge butterfly and
safety lock blood collection set and a 30-­mL syringe. Blood samples
(10 mL) were incubated at room temperature for 1 hour and centri-
fuged at 2000 g for 20 minutes. The isolated serum samples were
stored at −80°C until biochemical analysis. All samples were imme-
diately sent to medical laboratories as follows: plaque for bacterial
analysis and 2 mL blood samples for endotoxin assays were sent to
the BML Corporation (Tokyo, Japan);24,25 the gingival crevicular fluid
and serum samples were sent to Filgen Inc. (Nagoya, Japan) for CRP
tests and multiplex arrays;26,27 a portion of the sera samples were
sent to Leisure Inc. (Tokyo, Japan) for antibody assays. 25,28
2.5 | Analysis of inflammatory mediators in
serum and gingival crevicular fluid
Hs-­CRP levels in serum and gingival crevicular fluid samples were
measured using a quantitative sandwich enzyme immunoassay
First visit
Oral hygiene instructions and supragingival scaling
1 mo 2 subjects dropped out
(Reason: unmatched schedules)
Baseline
1 wk
3-d before the procedure
3d
1-stage full-mouth SRP
1d 1 subject retired
(Reason: pyrexia)
1-d post-treatment
6 wk
6-wk post-treatment
 |
4       MOROZUMI et al.
technique (Quantikine enzyme-­linked immunosorbent assay human
CRP/CRP immunoassay; R&D Systems Inc., Minneapolis, MN, USA)
in accordance with the manufacturer’s protocol. Briefly, a 100-­fold
dilution of the serum sample using appropriate standard diluents
and gingival crevicular fluid supernatant fluid was prepared. Each
sample solution (50 μL) was added to each well, and the microplate
was incubated for 2 hours at room temperature. Conjugate antibod-
ies were then added, and the microplate was incubated for another
2 hours. Substrate solution (200 μL) was then added to each well,
and the plate was incubated for 30 minutes for color develop-
ment. A stop solution (50 μL) was added immediately after the color
change. The enzyme-­linked immunoassay plate was read at 450 and
540 nm using an EMax Microplate Reader (Molecular Devices, LLC.,
Sunnyvale, CA, USA) with SoftMax Pro 6.3 Software (Molecular
Devices) allowing for detection of values as low as 0.01 ng/mL.
Multiplex quantification of serum and gingival crevicular fluid
cytokines (ie, IFN-­γ, IL-­4, IL-­5, IL-­6, IL-­12p70 and TNF-­α) was per-
formed using a commercially available kit (ProcartaPlex multiplex
immunoassays panels; Affymetrix eBioscience, Santa Clara, CA,
USA) in accordance with the manufacturer’s protocols. In brief, the
immunobead mixture (50 μL) was added to each well, which was fol-
lowed by the addition of 25 μL of serum sample or gingival crevic-
ular fluid supernatant fluid. The microplate was gently shaken on a
microplate shaker (500 rpm) for 120 minutes at room temperature.
Detection antibodies (25 μL) were added and the plate was incu-
bated at room temperature for an additional 30 minutes. Next, 50 μL
of streptavidin-­phycoerythrin was added and the microplate was in-
cubated for 30 minutes in a dark environment with constant shak-
ing (150 rpm). Finally, reading buffers were added to each well, and
the absorbance was read at 532 and 635 nm using an autoanalyzer
(Bio-­Plex 200 System; Bio-­Rad, Hercules, CA, USA) with Bio-­Plex
Manager software v6.0 (Bio-­Rad).
For these assays, duplicate readings were performed on a sub-
set of samples to demonstrate a high level of correlation between
measurements; intra-­class correction varied between 0.95 and 1.0
(P < .001). 29
These analyses were primary endpoints in the study. From the
obtained data, serum and gingival crevicular fluid levels of CRP and
6 inflammatory cytokines at 3 time points, particularly those inflam-
matory mediators that increased at 1 day post-­FM-­SRP, were eval-
uated to clarify the systemic influence of FM-­SRP on acute-­phase
responses following treatment.
2.6 | Quantification of periodontal bacteria from
subgingival plaque
Quantitative analysis of total bacterial counts and periodontopathic
bacterial counts, including Porphyromonas gingivalis and Prevotella
intermedia, were performed using a modified Invader PLUS assay. A
30,31
detailed measurement method is described in previous reports.
The proportions of the 2 pathogens compared to total bacterial
counts were calculated;25,32 the ratio (%) of each species was used
for various comparisons as well as for bacterial counts (log10).
2.7 | Measurement of periodontal bacteria-­specific
IgG titers in serum
Periodontal pathogen-­specific serum IgG antibody titers were deter-
mined using an enzyme-­linked immunosorbent assay.33 As bacterial
antigens, sonicated preparations of P. gingivalis FDC381 and P. inter-
media ATCC25611 were used. A detailed measurement method is
described in previous reports. 25,28
2.8 | Plasma endotoxin levels
Endotoxin assays were performed with separated plasma from hep-
arinized whole blood samples centrifuged at 150 g for 10 min. The
high-­sensitivity assay was performed using a kinetic turbidimetric
limulus assay using a MT-­358 Toxinometer (Wako Pure Chemical
Industries, Ltd., Osaka, Japan), a device theoretically capable of
accurately measuring concentrations as low as 0.01 pg/mL.34 This
limulus assay assesses a specific endotoxin and has been confirmed
to not cross-­react with β-­glucan.35 The cut-­off endotoxin level for
the diagnosis of sepsis is 1.1 pg/mL. Changes in mean arterial pres-
sure and the ratio of arterial oxygen partial pressure to fractional
inspired oxygen were also evaluated. The inotropic score was calcu-
lated as (dopamine dose × 1) + (dobutamine dose × 1) + (epinephrine
dose × 100) + (norepinephrine dose × 100), where all doses were
expressed as micrograms per kilogram per minute.36
2.9 | Statistical analysis
Descriptive analysis of the collected data was performed and the
results are presented as means ± SD. Serum IgG titers, CRP and
cytokine levels among 3 time points were calculated using the
Wilcoxon signed-­
rank test with further adjustment for multiple
comparisons, for which the accepted significance was P < .016. The
Wilcoxon signed-­rank test was used to compare clinical parameters,
periodontal bacterial levels and body temperature between 2 time
points. Distribution of body temperature was calculated by the
McNemar test. P < .05 was considered statistically significant. All
analyses were performed using IBM SPSS Statistics ver. 19.0 soft-
ware (IBM Japan, Tokyo, Japan). A sample size calculation suggested
that at least 20 patients were needed to demonstrate a 9.6 mg/L
increase in serum levels of CRP after FM-­SRP (90% power, a 0.01,
standard deviation of 8.1.37
3 | R E S U LT S
Of the 31 subjects, 2 dropped out because they were unable to
comply with the visit schedule. In addition, 1 patient was discontin-
ued from the program due to pyrexia on the day following FM-­SRP.
Eventually, 28 subjects successfully completed the study protocol.
Baseline demographic characteristics and bacterial variables
and those 6 weeks after FM-­SRP are presented in Table 1. Scores
for PlI (P = .040), GI (P = .006), BOP (% positive), probing depth,
MOROZUMI et al. |
      5

TA B L E   1   Clinical parameters and

Baseline (n = 29) 6 wk post-­treatment (n = 28) P-­value
bacterial levels for baseline measurements
and 6 wk after full-­mouth scaling and root Gender (male/female) 13/16 —
planing Age (y) 59.4 ± 8.9 —
Number of teeth (n) 26.8 ± 2.9 —
Bone resorption (%) 26.3 ± 8.1
PlI 0.38 ± 0.33 0.29 ± 0.29 .040*
GI 0.92 ± 0.56 0.67 ± 0.43 .006*
BOP (% positive) 47.27 ± 19.45 23.25 ± 16.50 <.001*
PD (mm) 3.69 ± 0.76 2.82 ± 0.63 <.001*
CAL (mm) 4.15 ± 0.99 3.46 ± 0.93 <.001*
PD-­sampled sites (mm) 6.21 ± 1.65 4.32 ± 2.22 <.001*
CAL-­sampled sites (mm) 6.57 ± 1.94 5.18 ± 2.38 <.001*
Total bacteria (log10) 5.19 ± 0.58 4.50 ± 0.80 .001*
P. gingivalis (log10) 2.78 ± 1.66 0.91 ± 0.93 <.001*
P. gingivalis ratio (%) 2.94 ± 3.67 0.29 ± 1.37 <.001*
P. intermedia (log10) 1.66 ± 1.05 1.13 ± 0.94 .064
P. intermedia ratio (%) 0.15 ± 0.23 0.10 ± 0.23 .220

Values represent mean ± SD.

BOP, bleeding on probing; CAL, clinical attachment level; GI, gingival index; PD, probing depth; PlI,
plaque index; ratio, each bacterial count/total bacterial count.
PD sampled sites and CAL sampled sites indicate the value of the sites, from which subgingival
plaque and gingival crevicular fluid were collected for each subject. Wilcoxon signed-­rank test was
used for statistical analysis (*P < .05).

TA B L E   2   Changes in levels of serum and gingival crevicular fluid inflammatory markers after full-­mouth scaling and root planing

P-­value

(b) 1 d post-­treatment (c) 6 wk post-­ Between (a) Between (a) Between
(a) Baseline (n = 29) (n = 28) treatment (n = 28) and (b) and (c) (b) and (c)

Serum
hs-­CRP (ng/mL) 917.25 ± 1152.22 4756.05 ± 3236.34 845.45 ± 1863.36 <.001* .068 <.001*
IFN-­γ (pg/mL) 1.22 ± 2.21 23.64 ± 40.98 0.76 ± 1.05 <.001* .142 <.001*
IL-­5 (pg/mL) 0.17 ± 0.52 0.15 ± 0.82 0.20 ± 0.62 >.999 .893 .713
IL-­6 (pg/mL) 1.32 ± 6.84 6.78 ± 23.46 1.29 ± 6.83 .041 .180 .050
IL-­12p70 (pg/mL) 0.39 ± 0.89 1.55 ± 2.04 0.40 ± 0.89 .001* .593 .001*
TNF-­α (pg/mL) 1.89 ± 1.81 2.12 ± 2.01 2.02 ± 1.90 .023 .398 .080
GCF
hs-­CRP (ng/mL) 0.89 ± 1.84 8.55 ± 14.61 0.59 ± 1.43 <.001* .028 <.001*
IFN-­γ (pg/mL) 2.84 ± 2.44 3.15 ± 2.03 2.93 ± 3.57 .084 .456 .052
IL-­5 (pg/mL) 0.27 ± 0.62 5.51 ± 10.89 0.05 ± 0.19 .001* .041 .001*
IL-­6 (pg/mL) 69.53 ± 261.30 2028.56 ± 2656.10 20.97 ± 54.55 <.001* .054 <.001*
IL-­12p70 (pg/mL) 2.19 ± 1.76 10.23 ± 19.70 1.91 ± 1.32 <.001* .328 <.001*
TNF-­α (pg/mL) 4.41 ± 4.36 33.21 ± 35.57 4.99 ± 9.61 <.001* .386 <.001*

Values represent mean ± SD.

hs-­CRP, high-­sensitive C-­reactive protein; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.
Changes for each marker, between baseline values and levels at each interval, were evaluated by the Wilcoxon signed-­rank test with further adjust-
ments for multiple comparisons; significance was indicated at P < .016 (*).

clinical attachment level, probing depth-­sampled sites and clinical baseline values. Meanwhile, the numbers of total bacteria (P = .001)
attachment level-­sampled sites (P < .001 for the latter 5 parameters) and P. gingivalis (P < .001), as well as the P. gingivalis ratio (P. gingivalis
were significantly improved 6 weeks after treatment compared to count/total bacterial count; P < .001) significantly decreased.
 |
6       MOROZUMI et al.
Baseline levels of serum and gingival crevicular fluid inflamma-
tory mediators and those at 1 day and 6 weeks post-­FM-­SRP are
shown in Table 2. Comparing levels at 1 day post-­FM-­SRP to base-
line values, a significant elevation was observed for serum hs-­CRP
(P < .001), IFN-­γ (P < .001) and IL-­12p70 (P = .001). After 6 weeks,
these values were significantly reduced compared to those 1 day
post-­treatment (P < .001, P < .001 and P = .001, respectively).
Although there is a tendency for IL-­6 levels to increase (from baseline
levels) at 1 day post-­treatment, this change did not reach statistical
significance. No substantial changes were noted in IL-­5 and TNF-­α
levels among the 3 time points. For gingival crevicular fluid levels, a
marked increase in hs-­CRP (P < .001), IL-­5 (P = .001), IL-­6, IL-­12p70
and TNF-­α (P < .001 for the latter 3 cytokines) was observed 1 day
after treatment compared to baseline values. In contrast, levels of
those markers 1 day post-­treatment were significantly decreased
after 6 weeks (P < .001, P = .001, P < .001 for the latter 3 markers,
respectively). No significant changes in gingival crevicular fluid levels
of IFN-­γ were observed among the 3 time points. IL-­4 was virtually
undetectable in both serum and gingival crevicular fluid samples.
Table 3 shows the changes in serum IgG titers for P. gingivalis
and P. intermedia, comparing baseline values with levels at 1 day
and 6 weeks post-­FM-­SRP. A significant decrease in P. gingivalis IgG
titers 6 weeks after treatment, compared to the value at baseline
(P < .001) or 1 day post-­treatment (P = .007) was observed.
The mean body temperature 3 days before and on the day of FM-­
SRP was described as the basal body temperature (Table 4); average
body temperature was significantly elevated after 1 day of treatment
(P = .007). We categorized body temperature before and 1 day after
treatment based on 2 ranges, specifically, below 37.0°C and 37.0°C or
above. Distribution of patient body temperature exhibited no differences
(P = .125). Although all subjects had a body temperature below 37.0°C
before treatment, 4 subjects had a body temperature above 37.0°C after
1 day. In particular, 1 subject presented with fever above 38.0°C.
Blood endotoxin levels for 27 patients at all time points were
below measurable limits (≤1.0 pg/mL). Only 1 patient presented with
elevated blood endotoxin levels. Specifically, the baseline endotoxin
levels and those at 1 day and 6 weeks post-­FM-­SRP were 1.3, 1.1
and ≤1.0 pg/mL, respectively.
TA B L E   3   Changes in periodontal bacteria-­specific serum IgG titers from baseline measurements to 1 d and 6 wk after full-­mouth scaling
and root planing
(a) Baseline (b) 1 d post-­treatment
(n = 29) (n = 28)
P. gingivalis IgG 29.18 ± 33.20 28.95 ± 33.14
titers (EU)
P. intermedia IgG 0.46 ± 0.56 0.41 ± 0.55
titers (EU)
Values represent mean ± SD.
EU, enzyme-­linked immunosorbent assay unit.
Changes for each IgG titer, between baseline values and levels at each interval, were evaluated by the Wilcoxon signed-­rank test with further adjust-
ments for multiple comparisons; significance was indicated at P < .016 (*).
4 | D I S CU S S I O N
We examined comprehensively the magnitudes of systemic and
local acute-­phase responses following FM-­SRP. Our findings suggest
that FM-­SRP results in clinical and microbiological improvement,
while inducing a moderate systemic and local acute inflammatory
response during the first 24 hours. These data are of utmost impor-
tance as FM-­SRP includes both a curative and invasive phase.
Increased serum levels of inflammatory and hemostatic system
markers after FM-­
SRP were previously reported, specifically for
CRP, IL-­1RA, IL-­6, serum amyloid-­A and D-­dimers.12,14,37 Our data
showed similar results, and indicate that the FM-­SRP stimulus was
sufficient to activate an acute inflammatory response. A possi-
ble explanation for these responses might be both bacteremia and
host immune response combined with local tissue damage follow-
ing subgingival instrumentation;38 this could contribute to an in-
crease in proinflammatory mediators39 and acute-­phase proteins.40
Consequently, traditional and modern models used to study human
inflammation have reported similar short-­term acute responses of
variable magnitudes.14,41,42
Regarding reports of serum inflammatory markers after FM-­SRP,
there is a large discrepancy. For example, D’Aiuto et al12 reported
a 10-­fold increase in CRP at 1 day post-­FM-­SRP, whereas a 5-­fold
increase was noted in the present study. This variability could be
attributed to several factors that influence bacteremia and the sub-
sequent acute-­phase reaction, such as the instrumentation used, the
invasiveness of the procedure, the degree of periodontal inflamma-
tion, the quantity and composition of gingival microbiota, and im-
mune capacity. In fact, the subjects used in studies by D’Aiuto et al
were limited to those with generalized severe chronic periodontitis.
Meanwhile, in the present study, patients were diagnosed with gen-
eralized moderate-­to-­severe chronic periodontitis.
Interestingly, levels of IL-­6 in gingival crevicular fluid and hs-­CRP
in serum were markedly elevated at 1 day post-­treatment. This might
be associated with the hypothesis that both local (gingival) produc-
tion of IL-­6 and systemic dissemination are followed by the release
of acute-­phase proteins such as CRP and haptoglobin from the liver
to protect the host against local pathological stimuli.43
P-­value
(c) 6 wk post-­ Between (a) Between (a) Between
treatment (n = 28) and (b) and (c) (b) and (c)
25.03 ± 28.99 .673 <.001* .007*
0.44 ± 0.68 .050 .255 .532
MOROZUMI et al.
Fever is a typical response to inflammation and infection. Upon
bacterial infection, host immune cells produce pyretic cytokines
44
including TNF-­α , IL-­1β and IL-­6. These circulating cytokines stim-
ulate the production of prostaglandin E2 in the hypothalamus, and
this lipid mediator elevates body temperature.45 In this study, it was
observed that mean body temperature significantly rose 1 day after
treatment although this was marginal. Indeed, 4 patients exhibited a
body temperature ≥37.0°C after treatment, whereas body tempera-
ture was below 37.0°C before treatment for all patients. The most
noteworthy is that 1 patient experienced pyrexia, with a body tem-
perature above 38.0°C, and thus body temperature was elevated
by 2°C due to FM-­SRP. This was the most important complication
identified in the study. There are conflicting results regarding altered
body temperature after FM-­SRP. Quirynen et al46 reported that over
half of patients experienced a rise in body temperature, to above
47
37.0°C, whereas Koshy et al reported no patients with pyrexia.
Similar results have been obtained using full-­mouth disinfection,
which involves not only mechanical debridement but also chlorhex-
idine application to all oral niches.46,47 This discrepancy might have
been caused by several factors, referred to previously herein. We
reported related research in which premedication with azithromycin
48
reduced bacteremia secondary to quadrant SRP. In addition, this
treatment was shown to prevent pyrexia after FM-­SRP.49,50 Further
specific studies addressing this outcome are required.
In the present study, clinical parameters improved drastically
after FM-­SRP. Reductions in whole-­mouth BOP, probing depth and
clinical attachment level values at 6 weeks post-­
treatment were
approximately 24%, 0.9 mm and 0.6 mm, respectively. These data
are similar to a previous report that noted reductions of 21% for
BOP, 0.8 mm for probing depth and 0.7 mm for clinical attachment
level.51 Apatzidou & Kinane52 reported clinical outcomes that were
more favorable, specifically, reductions of 51% for BOP, 1.6 mm for
probing depth and 1.0 mm for clinical attachment level. Our results
indicated that the mean baseline probing depth value at the 2 deep-
est periodontal pockets selected for sampling of subgingival plaque
and gingival crevicular fluid was 6.2 mm; the reduction after 6 weeks
post-­treatment was 1.9 mm. There are numerous studies that have
reported comparable probing depth changes at sites with initial
TA B L E   4   Changes and distribution of
patient body temperatures before and 1 d
n = 29
after full-­mouth scaling and root planing
Body temperature (°C)
Distribution (n)
Below 37.0°C
37.0°C or above
Values represent mean ± SD.
Before treatment, the mean body temperature 3 d before and on the day of full-­mouth scaling and
root planing. Intragroup comparisons for body temperature were made using the Wilcoxon signed-­
rank test (*P < .05). Distributions of patient body temperatures were calculated by the McNemar test
(level of significance, <.05).
      7|
values >6 mm, after FM-­SRP; specifically, the decrements were
1.74 mm11 and 1.7 mm.15
Subgingival bacterial counts of P. gingivalis were markedly de-
creased after treatment as with previous reports.16,53,54 Although
there seems to be a tendency for P. intermedia counts to be reduced,
this did not reach statistical significance. This could be attributed to
lower bacterial counts for P. intermedia (approximately 1/10 those
of P. gingivalis). These data are consistent with findings of Rhemrev
et al and Botero et al, who reported that P. intermedia counts in the
sulci of diseased chronic periodontitis sites are low even though the
detection rate is high.55,56
There have been various reports describing the serum antibody
titer response to periodontal therapy.57 It has been documented
that IgG titers are increased due to a booster effect at 2-­4 months
post-­treatment.58,59 In contrast, some studies reported a grad-
ual reduction in the elimination of the source of infection after
2-­12  months.58,60,61 In this study, P. gingivalis-­specific IgG titers de-
creased at 6 weeks post-­treatment. Similar results were obtained in
a report by Wang et al,62 as a significant decrease was shown for
P. gingivalis IgG titers 1, 3 and 6 months after a single-­visit full-­mouth
ultrasonic debridement. Their findings imply that full-­mouth treat-
ment might induce an earlier effect on humoral responses to P. gingi-
valis because of wide-­scale removal of etiological agents.
Herein, reported circulating endotoxin markers were nearly below
measurable limits (≤1.0 pg/mL) at all time points. This could have
been because initial toxemia was cleared by the host. Blood sampling
was performed 1 day after treatment; however, some studies suggest
that plasma levels are already decreased 5 minutes after endotoxin
injection due to the activity of the reticuloendothelial system.63,64
Our data revealed that FM-­SRP has a substantial systemic ef-
fect. Studies have shown that FM-­SRP induces higher serum CRP
levels, compared to those observed with partial periodontal surgical
therapy.37 Furthermore, the reported sharp and temporary acute re-
sponse after treatment might be of particular interest as inflamma-
tion could lead to an acute state of vascular dysfunction and possibly
increase the risk of vascular events.65,66 Considering the merits and
demerits of FM-­SRP, the practice of this modality should depend on
individual decisions.
1 d
Before treatment post-­treatment P-­value
36.14 ± 0.22 36.36 ± 0.49 .007*
<36.0°C 8 6
≥36.0°C, <37.0 21 19
.125
≥37.0°C, <38.0 0 3
≥38.0°C 0 1
 |
8       MOROZUMI et al.
The authors are aware of some limitations of this study. First,
the patient sample size was relatively small for a multicenter study,
although formal sample size estimation was performed. Second, the
calibration of the operators who performed FM-­SRP was not car-
ried out. Thus, the effectiveness of this procedure might be biased.
Third, a group receiving partial-­mouth SRP was not included as a
control group in the study design. Hence, it is not possible to state if
the alterations observed 1 day after FM-­SRP would also occur, and
at what intensity, 1 day after quadrant SRP. Further research in this
area is advocated.
In conclusion, it is suggested that FM-­SRP results in clinical and
microbiological improvement 6 weeks post-­treatment, but produces
a moderate systemic acute-­phase response including elevated in-
flammatory mediators 1 day after treatment.
AC K N OW L E D G E M E N T S
The kind assistance of the clinical staff of the facilities is gratefully
acknowledged. The authors also wish to thank Drs. Tomoko Hasegawa
and Kaname Nohno, Niigata University Graduate School of Medical
and Dental Sciences, and Dr. Kazuhiro Ohmori, Okayama University
Hospital, for their advice and useful comments. The sponsor had no
role in study design, data collection and interpretation, or the decision
to submit the work for publication.
CONFLIC T OF INTEREST
The authors declare that they have no conflicts of interest.
AU T H O R C O N T R I B U T I O N
TM and AY wrote the manuscript and contributed equally to this work.
HY, KG, YI, MM, and TY participated in the study design and managed
the recruitment of subjects. TM, AY, TA, MM, and MT performed peri-
odontal treatment and data collection. KM, HT, SM, and YT performed
sample collection. YU and TH performed statistical analysis.
ORCID
T. Morozumi  http://orcid.org/0000-0002-7151-1292
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How to cite this article: Morozumi T, Yashima A, Gomi K, et al.
Increased systemic levels of inflammatory mediators following
one-stage full-­mouth scaling and root planing. J Periodont Res.
2018;00:1–9. https://doi.org/10.1111/jre.12543