Clinica Chimica Acta 506 (2020) xxx–xxx

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Clinica Chimica Acta

journal homepage: www.elsevier.com/locate/cca

Serum D-dimer as a diagnostic index of PJI and retrospective analysis of T

etiology in patients with PJI
⁎
Qian Hu, Yaoyang Fu, Lingli Tang
Department of Laboratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China

A R T I C LE I N FO A B S T R A C T

Keywords: Objectives: To investigate the diagnostic value of serum D-dimer in patients with periprosthetic joint infection
Prosthetic joint infection (PJI). Moreover, to provide evidence for the treatment of PJI by investigating distribution of pathogenic bacteria
D-dimer and antibiotic resistance situation among the patients.
CRP Methods: A retrospective study of the medical records of all patients undergoing arthroplasty from the Second
ESR
Xiangya Hospital of Central South University from 2014 to 2018, 40 patients with periprosthetic joint infection,
Bacteria
37 patients with aseptic loosening and 59 patients with extra-articular infection were selected. The results of
Antibiotic resistance
serum D-dimer, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were collected. As well as the
bacterial types and antimicrobial susceptibility test results from tissue or joint fluid samples around the pros-
thetic joint of the patients were collected. All the relevant data were analyzed.
Results: The serum D-dimer, CRP and ESR level were significantly higher in the patients with PJI. The mean D-
dimer level was 2.0795 μg/mL in PJI group compared with 0.6854 μg/mL in aseptic loosening group
(p = 0.000) and 0.4556 μg/mL in extra-articular infection group (p = 0.000). For diagnosing PJI, the serum D-
dimer test demonstrated better sensitivity (87.50%), and better specificity (89.19%); while the serum CRP and
ESR had a sensitivity of 80.00% and 82.50% and a specificity of 78.38% and 64.86%, respectively. Moreover, the
sensitivity and specificity of ESR and CRP combined was 75.00% and 83.78%, respectively. In addition, 29
strains of pathogens around the prosthesis after arthroplasty were detected, including 22 strains of Gram-positive
bacteria, 3 strains of Gram-negative bacteria, and 4 strains of fungi. The staphylococcus was the major pathogen
showing high resistance to Cefoxitin and ampicillin.
Conclusion: Patients with PJI have high levels of serum D-dimer, which is a promising marker for the diagnosis
of PJI. The Gram-positive bacteria are major pathogen in PJI after arthroplasty, and Staphylococcus aureus is the
most common organism. Clinical efficacy is significantly improved by reasonable choice of antibiotics and ef-
fective medicine education.

1. Introduction American Academy of Orthopaedic Surgeons (AAOS), the Muscu-

Arthroplasty is an effective method for the treatment of advanced
osteoarthrosis, which can restore the joint function and obtain a good
quality of life. In recent years, the number of operations has increased
year by year, but postoperative prosthetic joint infection (PJI) is a
catastrophic complication after arthroplasty. The occurrence of PJI not
only brings great physical and economic losses to patients, but also the
loss of medical resources.
The timely and correct diagnosis of PJI is critical to the development
of its follow-up treatment strategy. Current routine diagnostic methods
include serological testing, synovial fluid testing, and intraoperative
histological pathology [1–6]. Based on the above methods, the
larskeletal Infection Society (MSIS), the Infectious Diseases Association
(IDSA) and other organizations have published their own PJI diagnostic
guidelines, which have played an active role in promoting the diagnosis
and treatment of PJI. The currently widely used diagnostic criteria are
derived from the diagnostic guidelines issued by the 2011 Muscu-
loskeletal Infection Society (MSIS) (Table 1). But it must also be noted
that the diagnosis of PJI is still a serious challenge for clinicians.
At present, patients with suspected infections that are negative in
bacterial culture or have been treated with antibiotics are still unable to
confirm the diagnosis, and the formation of biofilms leads to a lower
diagnostic rate of PJI; in addition, when PJI is caused by low-toxic
pathogenic bacteria such as propionibacterium acnes, it is not enough

⁎
Corresponding author.
E-mail address: linglitang@csu.edu.cn (L. Tang).

https://doi.org/10.1016/j.cca.2020.03.023
Received 19 January 2020; Received in revised form 29 February 2020; Accepted 12 March 2020
Available online 13 March 2020
0009-8981/ © 2020 Elsevier B.V. All rights reserved.
Q. Hu, et al. Clinica Chimica Acta 506 (2020) xxx–xxx

Table 1 controlling the PJI after arthroplasty.

MSIS Criteria for the Diagnosis of PJI.
One of the following criteria is met, and PJI is clearly present. 2. Materials and methods

1 A sinus tract communicating with the joint or
2 Two positive periprosthetic cultures with phenotypically identical organisms
or
3 Meet 4 of the following 6 criteria:
a. Elevated serum CRP (> 10 mg/L) and ESR (> 30 mm/h)
b. Elevated synovial fluid WBC (> 3000 cells/μL) or +～++ changes in
leukocyte esterase strip
c. Elevated synovial fluid PMN percentage (> 80%)
d. The affected joints appear purulent
e. Positive histological analysis of periprosthetic tissue (> 5 neutrophils per
high-power field in 5 high-power fields (×400))
f. A single positive culture
If less than 4 of the criteria 3 are met, PJI may be present.
C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood
cell (WBC), and polymorphonuclear neutrophil (PMN).
to produce obvious inflammatory reaction, and the clinical manifesta-
tions are difficult to meet the MSIS standard, and the ESR and CRP
levels may be normal [7]. Serum CRP and ESR may not be accurate as a
diagnostic tool for PJI, and their sensitivity and specificity are low,
especially in the identification of low-grade and chronic PJI [7,8]. In
addition, synovial fluid biomarkers (slip fluid white blood cell count,
PMN%, CRP, α-defensin, LE, etc.) have developed greatly in the past
few decades and have become the cornerstone of diagnostic algorithms
to confirm or exclude PJI, especially α-defensin has a high diagnostic
sensitivity to PJI [9–12]. However, there are many problems in the
diagnosis of PJI using synovial biomarkers. The acquisition of synovial
fluid is invasive and painful for the patient, which also increases the
infection rate of joints, and there is insufficient synovial fluid for all
tests.
The above issues highlight the need for new and reliable serum
biomarkers. Numerous studies have shown that systemic and local in-
fections lead to enhanced fibrinolytic activity, and D-dimers are derived
from plasmin-dissolved cross-linked fibrin clots, mainly reflecting fi-
brinolytic function. Its clinical tests are mainly used for the screening of
venous thromboembolism (VTE), deep vein thrombosis (DVT) and
pulmonary embolism (PE). However, in recent years, the study of serum
D-dimer in predicting the poor prognosis of bacteremia has received
much attention [13].
Therefore, we are interested in whether PJI patients have high le-
vels of D-dimer, explore the specificity and sensitivity of D-dimer in the
diagnosis of PJI, and thus serve as a promising biomarker for early
diagnosis of infection. In addition, understanding the pathogenic
characteristics of PJI patients, selecting antibacterial drugs for specific
bacteria, to ensure the effective treatment of patients, is essential for
After approval by the Institutional Review Board, we conducted a
retrospective study of the medical records of all arthroplasty patients
from the Second Xiangya Hospital of Central South University from
2014 to 2018 in China. Among them, 40 patients with periprosthetic
joint infection after arthroplasty (group A), 37 patients with aseptic
loosening (group B), and 59 patients with extra-articular infection
(group C) were randomly selected from the same period, including 18
cases of pulmonary infection (community acquired pneumonia), 14
cases of intracranial infection, 11 cases of upper respiratory tract in-
fection and 16 cases of urinary tract infection. PJI was defined using the
latest diagnostic criteria of the Musculoskeletal Infection Association
(MSIS) (Table 1). We excluded patients without serum erythrocyte se-
dimentation rate (ESR), serum CRP, or serum D-dimer. We collected the
patient's gender and age, the type of joint involved and the serum D-
dimer, CRP, ESR measurements, as well as the type of bacteria and
antimicrobial susceptibility test results from tissue or joint fluid samples
around the prosthetic joint. Patient demographics are presented in
Table 2.
2.1. D-dimer quantification
All of the patients were required to maintain a normal lifestyle and
avoid strenuous physical exercise within 3 days before the test. They
were also asked not to drink alcoholic beverages for at least 1 day.
Patients should fast for overnight for at least 8 h and sit still for at least
30 min before specimen collection. The patient's blood was collected in
a vacuum blood collection tube containing sodium citrate antic-
oagulant, ensuring that the ratio of sodium citrate to blood was 1: 9,
and mixed by inversion. The collected specimens were free of hemo-
lysis, chyle, and jaundice. After the specimen trait is determined, blood
samples were followed by centrifugation at 2000-2500g for 15 min. The
D-dimer level in venous plasma was assessed by an immunoturbidi-
metric assay, STA Liatest D-Di (Stago, France) on a STA-R coagulation
analyzer (STA-A Evolution, France).
2.2. Statistical analysis
The Kruskal-Wallis H test was used to compare the results of the
measurement data between the groups, and the χ2 test was used to
compare the results of the categorical data between the groups.
Differences between the two groups were compared by t test under
homogeneity of variance and t' test under irregularity. P value less
than 0.05 was considered to be significant. The optimal threshold for D-

Table 2
Comparison of values between groups.
Group A(N = 40) Group B(N = 37) Group C(N = 59) Test statistics P Value

Sex (no. of patients) Pearson χ = 5.305

2
0.070
Male 21 15 38
Female 19 22 21
Age 60.78(16–80) 65.57(26–93) 47.29(4–86) H = 23.877 0.000
Involved joint (no. of patients) Pearsonχ2 = 18.682 0.000
Knee 14 0 No
Hip 24 37 No
Others 2 0 No
D-dimer (μg/mL) 2.0795(0.15–8.31) 0.6854(0.17–1.77) 0.4556(0.16–3.15) H = 67.388 0.000
CRP (mg/L) 55.0245(2.33–274) 8.053(1–51.1) 28.4103(1.09–192) H = 26.917 0.000
ESR (mm/h) 56.65(7–104) 26.7027(4–80) 35.678(5–98) H = 24.294 0.000

Group A (PIJ); Group B (Aseptic loosening); Group C (Extra-articular infection).

Extra-articular infections included 18 cases of pulmonary infection (community-acquired pneumonia), 14 cases of intracranial infection, 11 cases of upper respiratory
tract infection, and 16 cases of urinary tract infection.
The values are given as the mean, with the range in parentheses.

2
Q. Hu, et al.
Fig. 1. D-dimer levels in each group: Group A (PIJ), Group B (Aseptic loos-
ening), Group C (Extra-articular infection). The black horizontal solid line in-
dicates the mean of each group. The horizontal dashed line indicates the
threshold for diagnosing PJI (The optimal threshold for PJI diagnosis was
0.955 g/ml by ROC curve analysis. The area under the ROC curve is 0.895,
which has a higher diagnostic accuracy). (For interpretation of the references to
colour in this figure legend, the reader is referred to the web version of this
article.)
dimer diagnosis as PJI is determined by ROC curve analysis based on its
correspondence with PJI diagnosis. The sensitivity, specificity, Yoden
index and 95% confidence interval of each diagnostic indicator were
calculated. All statistical analyses were performed using IBM SPSS
Statistics 23.0. All figures were drawn using Graphpad Prism 8.0.1.
3. Results
The serum D-dimer (Fig. 1), CRP (Fig. 2) and ESR (Fig. 3) level were
significantly higher in the patients with PJI. The mean D-dimer level
Fig. 2. CRP levels in each group: Group A (PIJ), Group B (Aseptic loosening),
Group C (Extra-articular infection). The black horizontal solid line indicates the
mean of each group. The horizontal dashed line indicates the threshold re-
commended by MSIS for diagnosing PJI (10 mg/L). (For interpretation of the
references to colour in this figure legend, the reader is referred to the web
version of this article.)
3
Clinica Chimica Acta 506 (2020) xxx–xxx
Fig. 3. ESR levels in each group: Group A (PIJ), Group B (Aseptic loosening),
Group C (Extra-articular infection). The black horizontal solid line indicates the
mean of each group. The horizontal dashed line indicates the threshold re-
commended by MSIS for diagnosing PJI (30 mm/h). (For interpretation of the
references to colour in this figure legend, the reader is referred to the web
version of this article.)
was 2.0795 μg/mL (range, 0.15–8.31 μg/mL) in PJI group compared
with 0.6854 μg/mL (range, 0.17–1.77 μg/mL) in aseptic loosening
group (p = 0.000) and 0.4556 μg/mL (range, 0.16–3.15 μg/mL) in
extra-articular infection group (p = 0.000). The mean CRP level was
55.0245 mg/L (range, 2.33–274 mg/L) in PJI group compared with
8.053 mg/L (range, 1–51.1 mg/L) in aseptic loosening group
(p = 0.000) and 28.4103 mg/L (range, 1.09–192 mg/L) in extra-ar-
ticular infection group (p = 0.023). The mean ESR level was
56.65 mm/h (range, 7–104 mm/h) in PJI group compared with
26.7027 mm/h (range, 4–80 mm/h) in aseptic loosening group
(p = 0.000) and 35.678 mm/h (range, 5–98 mm/h) in extra-articular
infection group (p = 0.001) (Table 2, Table 3).
Using the MSIS threshold values indicating the presence of PJI
(Table 1), assessments of serum CRP level and ESR demonstrated a
sensitivity of 80.00% and
82.50% and a specificity of 78.38% and 64.86%, respectively. The
sensitivity and specificity of ESR and CRP combined was 75.00% and
83.78%, respectively. Using the calculated threshold for D-dimer
(0.955 μg/ml), the serum D-dimer test demonstrated better sensitivity
(87.50%) , and better specificity (89.19%) , for diagnosing PJI. The
Youden index for D-dimer, CRP and ESR are 0.77 , 0.58 and 0.47 ,
respectively. The positive likelihood ratio (8.09), positive predictive
value (89.74%) and negative predictive value (86.84%) of D-dimer for
the diagnosis of PJI were higher, while the negative likelihood ratio was
lower (0.14) (Table 4).
The pathogen culture results of 28 patients with PJI are shown in
Table 5. The rate of positive cultures for PJI in the cohort was 33% (28
of 54). A total of 22 patients with Gram-positive bacteria (G + ) in-
fection. Staphylococcus is the main detective bacteria, of which 11
strains of Staphylococcus aureus, accounting for 50%. There were 3
cases of Gram-negative bacteria (G-) infection, and 4 cases were found
Table 3
Comparison of values between the two groups.
Group A VS Group B Group A VS Group C
t Value P Value t Value P Value
Age −1.473 0.145 3.712 0.000
D-dimer (μg/mL) 5.241 0.000 6.109 0.000
CRP (mg/L) 4.613 0.000 2.337 0.023
ESR (mm/h) 5.219 0.000 3.568 0.001
Q. Hu, et al. Clinica Chimica Acta 506 (2020) xxx–xxx

Table 4 Table 6
Common indicators for diagnostic tests. Antimicrobial resistance rate of pathogen.
D-Dimer CRP ESR CRP + ESR (serial test) Strain Antibiotic Drug-resistant Total Resistance rate
strains strains (%)
Number of patients
True negative 33 29 24 31 G+ Amikacin 5 14 35.7
False negative 5 8 7 6 Gentamicin 11 18 61.1
True positive 35 32 33 30 Tobramycin 7 11 63.6
False positive 4 8 13 10 Cefoxitin 7 8 87.5
Sensitivity (Se) 87.50% 80.00% 82.50% 75.00% Ampicillin 11 15 73.3
Specificity (Sp) 89.19% 78.38% 64.86% 83.78% penicillin 12 17 70.6
LR+ 8.09 3.70 2.35 Oxacillin 8 14 57.1
LR− 0.14 0.26 0.27 Amoxicillin/clavulanic 7 14 50.0
Youden index 0.77 0.58 0.47 acid
PV+ 89.74% 80.00% 71.74% Compound 5 17 29.4
PV− 86.84% 78.38% 77.42% sulfamethoxazole
Koalaranin 0 14 0.0
Patients: Group A and Group B. Vancomycin 1 22 4.5
Threshold:CRP (10 mg/L), ESR (30 mm/hr) and D-dimer (0.955 μg/ml). Clindamycin 11 17 64.7
LR+ (Positive likelihood ratio), LR− (Negative likelihood ratio), PV+ Ergomycin 15 21 71.4
Quinupudin/Dafupudin 0 13 0.0
(Positive predictive value), PV− (Negative predictive value).
Linezolid 2 22 9.1
Nitrofurantoin 0 11 0.0
Table 5 Ciprofloxacin 9 17 52.9
Pathogen culture results of PJI patients. Rifampin 5 15 33.3
tetracycline 11 17 64.7
Classification Strain Number of pathogens
G− Amikacin 0 3 0.0
Knee joint Hip joint Other Gentamicin 2 3 66.7
joints Imipenem 0 3 0.0
Cefazolin 3 3 100.0
G+ Staphylococcus aureus 5 5 1 Ceftazidime 1 3 33.3
Staphylococcus epidermidis 0 0 1 Cefepime 2 3 66.7
Coagulase-negative 1 2 0 Aztreonam 2 2 100.0
staphylococci Ampicillin 3 3 100.0
Streptococcus 2 2 0 Piperacillin 2 3 66.7
Enterococcu 1 2 0 Amoxicillin/clavulanic 1 3 33.3
acid
G− Escherichia coli 1 1 0
Ampicillin/sulbactam 1 3 33.3
Acinetobacter baumannii 0 1 0
Piperacillin/tazobactam 0 3 0.0
Fungi Candida 1 3 0 Compound 2 3 66.7
Total 11 16 2 sulfamethoxazole
Ciprofloxacin 2 3 66.7
1 case of hip joint infection with Candida glabrata and group C streptococcus. Levofloxacin 2 3 66.7
1 case of elbow infection with Staphylococcus epidermidis. tetracycline 2 3 66.7
1 case of shoulder joint infection with Staphylococcus aureus. Fungi 5-fluorocytosine 0 4 0.0
Amphotericin B 0 4 0.0
to be fungi. Antibiotic resistance of pathogens are provided in Table 6. Fluconazole 0 4 0.0
Itraconazole 1 4 25.0
The antimicrobial resistance rates of Gram-positive bacteria to cefoxitin Voriconazole 0 4 0.0
and ampicillin are higher (87.5% and 73.3%, respectively), while they
are highly sensitive to teicolanin and vancomycin (0.0% and 4.5%, This table counts the antibiotics provided for each susceptibility list.
respectively). Gram-negative bacteria have the highest resistance rate 4 strains of Staphylococcus aureus producing β-lactamase.
to cefazolin, aztreonam and ampicillin, all of which are 100%, but
highly sensitive to imipenem and meropenem, both of which are 0.0%. In addition, this study included a group of “positive control” pa-
tients, ie, patients with extra-articular infection. This allows us to assess
whether D-dimer is elevated by non-articular-associated infections. In
4. Discussion the extra-articular infection group, only 6.8% of patients had elevated
D-dimer levels, while CRP and ESR increased in 47.5% and 42.4%,
Clinically, D-dimer is commonly used as a screening test for venous respectively. Perez-Prieto, D et al. also found that the diagnostic criteria
thromboembolism. In recent years, there have been evidences that D- of blood inflammatory markers ESR and CRP may misdiagnose up to a
dimer levels may increase in the case of systemic or local inflammation quarter of PJI [7].
[14,15] and infection [13], particularly in joints [16]. In this study, we At the same time, the study analyzed the distribution and antibiotic
used statistical methods (ROC curve method) to determine the appro- resistance of pathogens causing PJI. The results showed that the most
priate threshold for D-dimer to diagnose PJI. Although this threshold common pathogen was Staphylococcus aureus, while the number of
may change with different institutions or the addition of other people's Gram-negative bacteria and fungal culture strains was small, which is
data, it is a good reference for clinicians who want to use this indicator basically consistent with the results reported in the existing literature
[17]. Our data analysis shows that serum D-dimer is more accurate than [19–23]. In terms of antibiotic resistance, both Gram-positive and
CRP and ESR in the diagnosis of PJI, and also superior to the combined Gram-negative bacteria showed strong drug resistance. Teicoplanin and
diagnosis of CRP and ESR. The sensitivity and specificity of D-dimer are vancomycin had higher sensitivity to Gram-positive bacteria, while
87.50% and 89.19%, respectively, but the actual value may be higher. imipenem and meropenem were highly sensitive to gram-negative
Because some patients classified as uninfected with a “positive” d-dimer bacteria, which could be used as first-line drugs. The main Gram-po-
result may have actually been infected with slow-growing, low-toxic sitive bacteria in this study are Staphylococcus, and the resistance of
pathogens, such as acne propionic acid bacillus, whose ESR And CRP Staphylococcus is mainly due to its easy formation of biofilm, which is
levels may be normal [18].

4
Q. Hu, et al.
long-term colonization on the infected site. It is difficult for anti-
bacterial drugs to penetrate the capsule, which is also an important
reason why staphylococcus infection was difficult to recover for a long
time [24]. In addition, the positive culture rate of PJI patients in this
study was low, only 33%. Possible reasons include: preoperative use of
antibiotics, the formation of bacterial biofilm, the inaccurate acquisi-
tion of intraoperative specimens, the method of specimen processing,
selection of culture medium and improper cultivation time [25–28].
Our study also has limitations. Currently, there is no gold standard
for the diagnosis of PJI. The MSIS standard is generally defined as the
best standard for diagnosing PJI and was used as the gold standard in
this study. Therefore, there may be some PJI patients assigned to the
aseptic loosening group. In addition, this study as a single-center study,
the number of cases is small, the small sample content may not fully
reflect the D-dimer level, pathogenic distribution characteristics and
antibiotic resistance characteristics of PJI at the present stage. Of
course, the small sample size is mainly due to the low incidence of PJI
and the difficulty in early diagnosis. Collecting cases in multiple centers
will solve this problem, which is the next step in this study.
In summary, PJI patients generally have higher D-dimer levels, with
a calculated diagnostic threshold of 0.955 μg/ml. Compared with serum
CRP and ESR, D-dimer has higher sensitivity and specificity in the di-
agnosis of PJI, which is expected to be a kind of serological biomarker
for the diagnosis of PJI. At the same time, the analysis of the pathogen
distribution and antibiotic resistance of PJI patients can effectively and
rationally guide clinical medication to a certain extent.
CRediT authorship contribution statement
Qian Hu: Conceptualization, Methodology, Formal analysis,
Investigation, Data curation, Writing - original draft, Writing - review &
editing. Yaoyang Fu: Writing - review & editing. Lingli Tang:
Conceptualization, Resources, Writing - review & editing, Supervision.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
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