ARTHROPLASTY

Synovial calprotectin
A POTENTIAL BIOMARKER TO EXCLUDE A PROSTHETIC JOINT
INFECTION

M. Wouthuyzen- Aims
Bakker, Recently, several synovial biomarkers have been introduced into the algorithm for the
J. J. W. Ploegmakers, diagnosis of a prosthetic joint infection (PJI). Alpha defensin is a promising biomarker, with
G. A. Kampinga, a high sensitivity and specificity, but it is expensive. Calprotectin is a protein that is present
L. Wagenmakers- in the cytoplasm of neutrophils, is released upon neutrophil activation and exhibits anti-
Huizenga, microbial activity. Our aim, in this study, was to determine the diagnostic potential of
P. C. Jutte, synovial calprotectin in the diagnosis of a PJI.
A. C. Muller Kobold
Patients and Methods
In this pilot study, we prospectively collected synovial fluid from the hip, knee, shoulder and
From University of elbow of 19 patients with a proven PJI and from a control group of 42 patients who
Groningen, underwent revision surgery without a PJI.
University Medical PJI was diagnosed according to the current diagnostic criteria of the Musculoskeletal
Center Groningen, Infection Society. Synovial fluid was centrifuged and the supernatant was used to measure
The Netherlands the level of calprotectin after applying a lateral flow immunoassay.

M. Wouthuyzen-Bakker, MD, Results

PhD, Fellow Infectious The median synovial calprotectin level was 991 mg/L (interquartile range (IQR) 154 to 1787)
Diseases, Department of
Internal Medicine and
in those with a PJI and 11 mg/L (IQR 3 to 29) in the control group (p < 0.0001). Using a cut-
Infectious Diseases off value of 50 mg/L, this level showed an excellent diagnostic accuracy, with an area under
J. J. W. Ploegmakers, MD,
Orthopaedic Surgeon,
the curve of 0.94. The overall sensitivity, specificity, positive predictive value (PPV) and
Department of Orthopaedic negative predictive value (NPV) was 89%, 90%, 81% and 95% respectively. The NPV was 97%
Surgery
G. A. Kampinga, MD, PhD,
in the nine patients with a chronic PJI.
Medical Microbiologist,
Department of Medical
Microbiology and Infection
Conclusion
Prevention Synovial calprotectin may be a valuable biomarker in the diagnosis of a PJI, especially in the
L. Wagenmakers-Huizenga,
Laboratory Technician,
exclusion of an infection. With a lateral flow immunoassay, a relatively rapid quantitative
Department of Laboratory diagnosis can be made. The measurement is cheap and is easy to use.
Medicine
P. C. Jutte, MD, PhD, Cite this article: Bone Joint J 2017;99-B:6605.
Orthopaedic Surgeon,
Department of Orthopaedic
Surgery Diagnosing or excluding a prosthetic joint infec- an undiagnosed PJI, some centres continue to
A. C. Muller Kobold, PhD,
tion (PJI) remains a challenge. Due to the forma- use broad spectrum antibiotics post-operatively
Clinical Chemist, Department of
Laboratory Medicine tion of a biofilm around the arthroplasty, pre- until the intra-operative cultures remain nega-
University Medical Center
operative diagnostic tests can be false negative, tive. However, this approach may result in
Groningen, Hanzeplein 1, 9700
RB, Groningen, The especially in chronic infections.1-4 For example, unnecessary antibiotic treatment and a longer
Netherlands.
inflammatory serum markers have a sensitivity stay in hospital. A diagnostic test with high
Correspondence should be sent of 35%1 and the sensitivity of a leucocyte accuracy is needed, especially with a high NPV.
to M. Wouthuyzen-Bakker;
email: m.wouthuyzen- count in synovial fluid is 67% in patients with a A point of care test, which can be used in the
bakker@umcg.nl clinical suspicion of aseptic loosening.1 In addi- operating theatre or in the clinic to exclude a
2017 The British Editorial tion, for chronic infections, the sensitivity and PJI, would be ideal in these situations. Alpha
Society of Bone & Joint negative predictive value (NPV) of synovial defensin is one of the most promising rapid
Surgery
doi:10.1302/0301-620X.99B5. fluid cultures are 79% and 88% respectively.4 diagnostic markers available, with a sensitivity
BJJ-2016-0913.R2 $2.00 Therefore, at least 10% of patients have false and specificity reaching nearly 100%, so that a
Bone Joint J negative diagnostic tests before revision surgery PJI can be diagnosed or ruled out at the bed-
2017;99-B:6605. and are considered to be aseptic, but are later side.5-8 Unfortunately it is also expensive,
Received 13 September 2016;
Accepted after revision 24 found to have a PJI from positive tissue cul- which makes it impracticable for routine use in
January 2017 tures.4 In order to avoid the risk of not treating most hospitals.

660 THE BONE & JOINT JOURNAL

 SYNOVIAL CALPROTECTIN
Table I. Baseline characteristics of patients with a prosthetic joint infection (PJI)
and control patients without an infection.
Patient characteristics
Age, mean (range)
Female, n (%)
Male, n (%)
Joint, n (%)
Hip
Knee
Shoulder
Elbow
Rheumatoid arthritis, n (%)
Immunosuppression, n (%)
Bone malignancy, n (%)
Calprotectin is a protein that is present in the cytoplasm
of neutrophils and is released upon their activation. It has
been established as a faecal marker in patients with inflam-
matory bowel disease,9 and, serum and synovial levels have
been used in patients with rheumatoid arthritis as a prog-
nostic marker and to monitor the response to treatment.10
By binding to manganese, zinc and iron, calprotectin
reduces the superoxide dismutase present on bacteria and
inhibits the bacterial defence against reactive oxygen spe-
cies,11-13 making it a potential biomarker for the diagnosis
of a PJI. In most hospitals, calprotectin is already routinely
measured using a faecal calprotectin enzyme-linked immu-
nosorbent assay (ELISA)-based test. Recently a lateral flow
immunoassay has become available which can be used as a
point of care test, with the result being available within
about 20 minutes.14
In this pilot study, we have studied the diagnostic poten-
tial of the level of synovial calprotectin in the diagnosis of a
PJI.
Patients and Methods
Between 1 July 2015 and 1 July 2016, synovial fluid from
the hip, knee, shoulder or elbow, was collected prospec-
tively from several subgroups of patients. Patients with an
acute PJI, a chronic PJI and a control group of patients
without an infection were included in the study. A PJI was
defined using the diagnostic criteria described by the Mus-
culoskeletal Infection Society (MSIS).15 An acute or chronic
PJI was defined as symptoms existing for or > three
weeks, respectively. Patients with an acute PJI comprised
only those with an infection presenting three months
post-operatively. Patients in the control group comprised
several subgroups: those undergoing an elective primary
arthroplasty, those with a spacer in situ without residual
signs of infection and who underwent a re-implantation
during two-stage revision surgery, those with aseptic loos-
ening of an arthroplasty, and those patients with a painful
arthroplasty. Intra-operative cultures were taken in patients
in groups 2, 3 and 4.
VOL. 99-B, No. 5, MAY 2017
661
PJI group (n =19) Control group (n = 42)
65 (24 to 87) 60 (23 to 90)
11 (58) 25 (60)
8 (42) 17 (40)
11 (58) 34 (81)
5 (26) 5 (12)
3 (16) 2 (5)
0 1 (2)
2 (10) 2 (5)
2 (10) 4 (10)
2 (10) 11 (26)
Patients with active gout, rheumatoid arthritis and psori-
atic arthritis were excluded, defined by the presence of
inflamed joints other than the arthroplasty.
Ethical approval was waived by our local ethics commit-
tee. Patients gave written consent for the analysis of syno-
vial fluid and processing of their medical records. Six
patients did not give informed consent and were excluded
from the study.
In total, 61 patients, 19 with a PJI and 42 controls, were
included in the study.
Synovial fluid was aspirated and sent directly to the lab-
oratory for analysis. The Rapid Calprotectin High Range
Quantum Blue assay was used to measure the synovial level
of calprotectin (BHLMANN laboratories AG, Schnen-
buch, Switzerland). The assay is a quantitative lateral flow
immunoassay and is designed for the selective measurement
of faecal calprotectin by means of a sandwich immunoas-
say.16
The synovial fluid was centrifuged for five minutes at
3000 rpm and a 1:100 dilution in chase buffer (QB reagent
provided in the QB kit) was used. 80 l of this sample was
then loaded onto the test cassette and incubated for 15 min-
utes. The quantitative result of the test band was measured
on the Quantum Blue reader (BHLMANN laboratories
AG), which measures the level of calprotectin in the faeces
in g/g. By multiplying the number by 100 and dividing it
by 7500, the value corresponds with mg/L calprotectin in
synovial fluid. The value of 7500 is based on the dilution
factor used when measuring calprotectin in faeces. The fae-
cal samples are extracted in a weight/volume ratio of 1:50
and the supernatant is 1:150 diluted. When a value of
> 1800 g/g is measured, the sample is further diluted with
chase buffer and re-assayed. This rapid assay has been val-
idated for faecal calprotectin and compared with values
measured using the Calprotectin ELISA (Bhlmann).16
Statistical analysis. Because of a non-Gaussian distribution
of data, a two-tailed Mann-Whitney U test or Kruskal-
Wallis test was used to calculate the difference between the
groups. A p-value < 0.05 was considered to be statistically
662 M. WOUTHUYZEN-BAKKER, J. J. W. PLOEGMAKERS, G. A. KAMPINGA, L. WAGENMAKERS-HUIZENGA, P. C. JUTTE, A. C. MULLER KOBOLD

Table II. Characteristics of patients with a prosthetic joint infection (PJI) and controls
without an infection.

PJI group (n = 19) Control group (n = 42)

Acute PJI (n = 10) Native joint
Polymicrobial (n = 4) Primary joint arthroplasty (n = 17)
S. epidermidis (n = 2) Osteoarthritis (n = 9)
S. aureus (n = 1) Malignancy (n = 5)
Escherichia coli (n = 1) Fracture (n = 1)
E. faecalis (n = 1) Malignancy and fracture (n = 1)
S. lugdunensis (n = 1) Cyst (n = 1)

Chronic PJI (n = 9) Spacer

S. epidermidis (n = 4) Before reimplantation (n = 9)
P. acnes (n = 2)
Pseudomonas aeruginosa (n = 1) Prosthetic joint
Streptococcus mutans (n = 1) Aseptic loosening prosthesis (n = 7)
Polymicrobial (n = 1) Painful prosthesis (n = 9)
S., Staphylococcus; E., Enterococcus; P., Propionibacterium

p < 0.0001
6000
p = 0.02 NS
5000 6000
4000 5000
3000 4000
mg/L

3000
mg/L

2000
1000 2000
1000
100
100
50
50
0 0
Control PJI

I
l)
l)

PJ
)

PJ
ol

ro
ro

tr

nt

te
nt

c
on

ni
cu
co
co

ro
(c

A
t(
t(

Ch
er

in
in

ac

jo
jo

Sp

tic
e
iv

he
at

st
N

o
Pr

Fig. 1a Fig. 1b

The synovial levels of calprotectin in patients with a prosthetic joint infection (PJI) and controls: a) overall results of the control group (n = 42) versus
the PJI group (n = 19); b) subgroup analysis of the control group versus the PJI group. Bars represents the median the interquartile range (NS,
not significant).

significant. The Fishers exact test was used to calculate the
confidence intervals (CIs) for the sensitivity, specificity,
positive predictive value (PPV), NPV and likelihood ratios
(LR). A ROC curve was depicted, and the area under the
curve (AUC) was calculated to determine the overall diag-
nostic accuracy of the test. Statistics were performed using
Prism 7 for Mac OS X (1994 to 2016 GraphPad Software,
Inc., La Jolla, California).
Results
The characteristics of the patients are shown in Tables I and
II. A total of ten patients (53%) with a PJI had an acute and
nine (47%) had a chronic PJI. The control group included
several joints, but mainly comprised hips (n = 34). In the PJI
group, hips (n = 11) and knees (n = 5) were the most prev-
alent (Table I). Table II shows the subgroups of the patients
and the causative pathogens for the infection.
Figure 1a shows the values for the level of synovial cal-
protectin. The median level was 991 mg/L (IQR, 154 to
1787) in the PJI group compared with 11 mg/L (IQR 3 to
29) in the control group (p < 0.0001). The median levels in
the acute and chronic PJI groups was not statistically differ-
ent: 1 033 mg/L (703 to 2623) versus 1 252 mg/L (92 to
1252), respectively (p = 0.66) (Fig. 1b). Subgroup analysis
of the control patients revealed a small difference between
the level in patients who underwent a primary arthroplasty

THE BONE & JOINT JOURNAL

 SYNOVIAL CALPROTECTIN 663

100

80

Sensitivity (%)
60

40

20
AUC 0.94

0
0 20 40 60 80 100
100% Specificity (%)

Fig. 2

Receiver operating characteristic (ROC) curve of the synovial levels of

calprotectin for diagnosing a prosthetic joint infection using a cutoff
value of 50 mg/L (AUC, area under the curve).

Table III. Diagnostic accuracy of synovial calprotectin for the diagnosis of a prosthetic joint infection. Cutoff value:
50 mg/L

Synovial calprotectin Overall Acute PJI Chronic PJI

Sensitivity (%) 89 (95% CI 0.69 to 0.98) 90 (95% CI 0.60 to 0.99) 89 (95% CI 0.57 to 0.99)
Specificity (%) 90 (95% CI 0.78 to 0.96) 90 (95% CI 0.78 to 0.96) 90 (95% CI 0.78 to 0.96)
Positive predictive value (%) 81 (95% CI 0.60 to 0.92) 69 (95% CI 0.42 to 0.87) 67 (95% CI 0.39 to 0.86)
Negative predictive value (%) 95 (95% CI 0.84 to 0.99) 97 (95% CI 0.87 to 1.0) 97 (95% CI 0.87 to 1.0)
Positive likelihood ratio 8.9 (95% CI 3.1 to 24.5) 9.0 (95% CI 2.7 to 24.8) 8.9 (95% CI 2.6 to 24.8)
Negative likelihood ratio 0.1 (95% CI 0.02 to 0.4) 0.1 (95% CI 0.01 to 0.51) 0.1 (95% CI 0.23 to 0.55)
CI, confidence interval

(median 5 mg/L, IQR 3 to 16) and those with pain and/or
loosening of the arthroplasty (median 23 mg/L, IQR 11 to
38; p = 0.02) (Fig. 1b). There was no difference between the
levels of synovial calprotectin in patients with a PJI of the
shoulder (n = 3), hip (n = 11) or knee (n = 5) (median values:
991 mg/L, IQR 85 to 1 587; 868 mg/L, IQR 98 to 2120 and
1 084 mg/L, IQR 987 to 2553, respectively) (p = 0.69).
The receiver operating curve (ROC) curve (Fig. 2), using
a cutoff value of 50 mg/L, shows that the level of synovial
calprotectin has an excellent diagnostic accuracy to identify
patients with a PJI (AUC 0.94).
The overall sensitivity, specificity, PPV and NPV of the
level of synovial calprotectin for PJI was 89%, 90%, 81%
and 95%, respectively (Table III). When acute and chronic
PJI are analysed separately, the level of synovial calprotec-
tin has a low PPV for acute (69%) and chronic PJI (67%).
The NPV is high: 97% for both acute as well as chronic PJI.
The level of synovial calprotectin has an overall positive LR
of 8.9, and a negative LR of 0.1.
Two of four patients with a false positive result (95 mg/
L and 197 mg/L) had aseptic loosening of their arthro-
plasty. Histological results showed a histiocytic reaction in
one patient, but there were no signs of inflammation and/or
infection in either patient. Both had negative intra-opera-
tive cultures. One patient with a false positive result (263
mg/L) had undergone a total hip arthroplasty (THA) for
osteoarthritis secondary to a dysplastic hip. The other
patient with a false positive result (233 mg/L) underwent
THA for a metastasis from carcinoma of the kidney. Histol-
ogy showed an active inflammatory process and necrotic
tissue secondary to radiotherapy.
In the two patients with false negative results, one had a
low-grade PJI of the hip caused by Propionibacterium
acnes. Histology did not reveal any signs of infection and/or
inflammation, suggesting a very low-grade infection. The
other had an early, acute infection after a primary THA
with persistent wound leakage due to polymicrobial flora
(Staphylococcus capitis, Staphylococcus epidermidis, Strep-
tococcus mitis and a Corynebacterium species in several
cultures). This patient was on immunosuppressive medica-
tion (prednisone 20 mg/day) because of ocular myasthenia.
One other patient was being treated with prednisone and
had a high level of synovial calprotectin (1876 mg/L) with
a chronic PJI.

VOL. 99-B, No. 5, MAY 2017

664 M. WOUTHUYZEN-BAKKER, J. J. W. PLOEGMAKERS, G. A. KAMPINGA, L. WAGENMAKERS-HUIZENGA, P. C. JUTTE, A. C. MULLER KOBOLD
Table IV. Proposed clinical interpretation of synovial calprotectin
values for the diagnosis of a prosthetic joint infection
Synovial calprotectin Interpretation
> 275 mg/L High suspicion for infection
50 to 275 mg/L Borderline suspicion for infection
< 50 mg/L Low suspicion for infection
Based on our data, we propose a scheme for the clinical
interpretation of the levels of synovial calprotectin for the
diagnosis of a PJI (Table IV).
Discussion
This is the first study to evaluate the synovial level of cal-
protectin in the diagnosis of a PJI. With an AUC of 94%,
using a cutoff value of 50 mg/L, it shows excellent potential
to diagnose a PJI. More importantly, with a NPV of 97%,
it is a promising marker to exclude PJI in patients with a
clinical suspicion of a chronic PJI, and shows promise for
use in daily clinical practice.
Calprotectin was measured in the laboratory in this
study, but it can relatively easily be measured in the clinic or
operating theatre. We used a centrifuge before subjecting
the synovial fluid to the lateral flow assay. This could be
addressed in future studies. An important advantage of the
use of calprotectin is the low cost. Apart from the purchase
of the calprotectin quantity reader, measuring the level of
synovial calprotectin costs about 20 per sample. Also, this
test is available as a diagnostic test for bowel disease in
most hospitals and thus easy to implement in routine care.
In particular, the high NPV of its measurement may have
several clinical benefits. By using a test with a high NPV, a
PJI can be rapidly ruled out in the clinic or emergency room
in patients who present with pain at the site of an arthro-
plasty. Ultimately, a negative test can be used pre-opera-
tively or in the operating theatre to rule out an infection in
patients with loosening of the arthroplasty.
Because this is a pilot study, it has limitations. The num-
bers of patients with a PJI in the study were small and more
data are needed on chronic infections and/or infections
caused by microorganisms with a low virulence. In addi-
tion, cutoff values need to be determined for patients with
rheumatoid arthritis and the influence of antibiotic and
immunosuppressive treatment on the levels of synovial cal-
protectin needs to be determined. Based on our limited
data, caution should be taken in the interpretation of a neg-
ative result in patients who are on immunosuppressive
treatment, as was illustrated by the false negative test in one
of the patients on prednisone in our study. Secondly, the test
may show a false negative result in very low-grade infec-
tions as illustrated by the patient with a Propionibacterium
acnes infection. Frangiamore et al17 showed a sensitivity of
only 63% for alpha-defensin in patients with a PJI of the
shoulder, when infection was caused by Propionibacterium
acnes in nine of 14 patients.
Another limitation of this study is the control group.
Because we also wanted to examine what normal levels
of synovial calprotectin were in non-infectious native
joints, 40% of our control group consisted of patients who
underwent a primary arthroplasty. Due to the low a priori
chance of an infection in these patients, this may bias the
specificity and NPV findings. However, the level of synovial
calprotectin in the patients who underwent primary arthro-
plasty was slightly lower than in those with a clinical suspi-
cion of infection. Furthermore, when the NPV was
calculated for chronic PJI using only the patients with pain
and/or loosening of the arthroplasty as a control group, the
NPV was still 93%.
Based on our preliminary results, the additional value of
using the level of synovial calprotectin in diagnosing a PJI is
probably limited. The PPV for PJI in general was 82%,
which is lower than when using other available biomark-
ers.18 Patients with synovial inflammation due to other
causes than an infection may also have high synovial cal-
protectin levels, as has been outlined in our results. Syno-
vial calprotectin has been used as a biomarker for the
activity of disease, therapeutic response and prognosis in
patients with rheumatoid arthritis. Abildtrup et al10
showed in a recent meta-analysis, that the mean synovial
level of calprotectin in patients with rheumatoid arthritis is
110 mg/L. Therefore, this should be borne in mind when
using the level of calprotectin to diagnose a PJI in a patient
with rheumatoid arthritis. However, the number of patients
with rheumatoid arthritis in our study was too low to draw
any conclusions about the ideal cutoff value for diagnosing
a PJI. Nonetheless, none of the patients with a false positive
result in our study had rheumatoid arthritis.
In conclusion, our data suggest that the level of synovial
calprotectin may be used as a biomarker to exclude a PJI. It
is important to note that the Quantum Blue calprotectin
test was used off-label in this study, as the measurement is
currently only validated for faecal calprotectin and further
confirmation would be needed before using it clinically in
this way.
Take home message:
- Synovial calprotectin is a potential biomarker that can be eas-
ily implemented in the diagnostic algorithm for patients with a
clinical supsicion of a chronic PJI.
-With its high specificity and negative predictive value, synovial calprotec-
tin may be used to exclude a PJI.
Author contributions:
M. Wouthuyzen-Bakker: Study design, Data collection, Interpretation of data,
Writing the paper.
J. J.W. Ploegmakers: Study design, Inclusion of patients.
G. A. Kampinga: Interpretation of data.
L. Wagenmakers-Huizenga: Measurement of synovial calprotectin.
P. C. Jutte: Study design, Inclusion of patients, Interpretation of data.
A. C. Muller Kobold: Study design, Quality assessment laboratory measure-
ments synovial calprotectin, Writing material and methods section on the
measurement of synovial calprotectin.
No benefits in any form have been received or will be received from a commer-
cial party related directly or indirectly to the subject of this article.
This article was primary edited J. Scott.
THE BONE & JOINT JOURNAL
 SYNOVIAL CALPROTECTIN
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