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
[email protected] 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 661

Table I. Baseline characteristics of patients with a prosthetic joint infection (PJI)

and control patients without an infection.

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

Age, mean (range) 65 (24 to 87) 60 (23 to 90)
Female, n (%) 11 (58) 25 (60)
Male, n (%) 8 (42) 17 (40)
Joint, n (%)
Hip 11 (58) 34 (81)
Knee 5 (26) 5 (12)
Shoulder 3 (16) 2 (5)
Elbow 0 1 (2)
Rheumatoid arthritis, n (%) 2 (10) 2 (5)
Immunosuppression, n (%) 2 (10) 4 (10)
Bone malignancy, n (%) 2 (10) 11 (26)

Calprotectin is a protein that is present in the cytoplasm Patients with active gout, rheumatoid arthritis and psori-
of neutrophils and is released upon their activation. It has atic arthritis were excluded, defined by the presence of
been established as a faecal marker in patients with inflam- inflamed joints other than the arthroplasty.
matory bowel disease,9 and, serum and synovial levels have Ethical approval was waived by our local ethics commit-
been used in patients with rheumatoid arthritis as a prog- tee. Patients gave written consent for the analysis of syno-
nostic marker and to monitor the response to treatment.10 vial fluid and processing of their medical records. Six
By binding to manganese, zinc and iron, calprotectin patients did not give informed consent and were excluded
reduces the superoxide dismutase present on bacteria and from the study.
inhibits the bacterial defence against reactive oxygen spe- In total, 61 patients, 19 with a PJI and 42 controls, were
cies,11-13 making it a potential biomarker for the diagnosis included in the study.
of a PJI. In most hospitals, calprotectin is already routinely Synovial fluid was aspirated and sent directly to the lab-
measured using a faecal calprotectin enzyme-linked immu- oratory for analysis. The Rapid Calprotectin High Range
nosorbent assay (ELISA)-based test. Recently a lateral flow Quantum Blue assay was used to measure the synovial level
immunoassay has become available which can be used as a of calprotectin (BHLMANN laboratories AG, Schnen-
point of care test, with the result being available within buch, Switzerland). The assay is a quantitative lateral flow
about 20 minutes.14 immunoassay and is designed for the selective measurement
In this pilot study, we have studied the diagnostic poten- of faecal calprotectin by means of a sandwich immunoas-
tial of the level of synovial calprotectin in the diagnosis of a say.16
PJI. The synovial fluid was centrifuged for five minutes at
3000 rpm and a 1:100 dilution in chase buffer (QB reagent
Patients and Methods provided in the QB kit) was used. 80 l of this sample was
Between 1 July 2015 and 1 July 2016, synovial fluid from then loaded onto the test cassette and incubated for 15 min-
the hip, knee, shoulder or elbow, was collected prospec- utes. The quantitative result of the test band was measured
tively from several subgroups of patients. Patients with an on the Quantum Blue reader (BHLMANN laboratories
acute PJI, a chronic PJI and a control group of patients AG), which measures the level of calprotectin in the faeces
without an infection were included in the study. A PJI was in g/g. By multiplying the number by 100 and dividing it
defined using the diagnostic criteria described by the Mus- by 7500, the value corresponds with mg/L calprotectin in
culoskeletal Infection Society (MSIS).15 An acute or chronic synovial fluid. The value of 7500 is based on the dilution
PJI was defined as symptoms existing for or > three factor used when measuring calprotectin in faeces. The fae-
weeks, respectively. Patients with an acute PJI comprised cal samples are extracted in a weight/volume ratio of 1:50
only those with an infection presenting three months and the supernatant is 1:150 diluted. When a value of
post-operatively. Patients in the control group comprised > 1800 g/g is measured, the sample is further diluted with
several subgroups: those undergoing an elective primary chase buffer and re-assayed. This rapid assay has been val-
arthroplasty, those with a spacer in situ without residual idated for faecal calprotectin and compared with values
signs of infection and who underwent a re-implantation measured using the Calprotectin ELISA (Bhlmann).16
during two-stage revision surgery, those with aseptic loos- Statistical analysis. Because of a non-Gaussian distribution
ening of an arthroplasty, and those patients with a painful of data, a two-tailed Mann-Whitney U test or Kruskal-
arthroplasty. Intra-operative cultures were taken in patients Wallis test was used to calculate the difference between the
in groups 2, 3 and 4. groups. A p-value < 0.05 was considered to be statistically

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

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

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

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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 Another limitation of this study is the control group.
values for the diagnosis of a prosthetic joint infection
Because we also wanted to examine what normal levels
Synovial calprotectin Interpretation of synovial calprotectin were in non-infectious native
> 275 mg/L High suspicion for infection joints, 40% of our control group consisted of patients who
50 to 275 mg/L Borderline suspicion for infection underwent a primary arthroplasty. Due to the low a priori
< 50 mg/L Low suspicion for infection 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-
Based on our data, we propose a scheme for the clinical cion of infection. Furthermore, when the NPV was
interpretation of the levels of synovial calprotectin for the calculated for chronic PJI using only the patients with pain
diagnosis of a PJI (Table IV). and/or loosening of the arthroplasty as a control group, the
NPV was still 93%.
Discussion Based on our preliminary results, the additional value of
This is the first study to evaluate the synovial level of cal- using the level of synovial calprotectin in diagnosing a PJI is
protectin in the diagnosis of a PJI. With an AUC of 94%, probably limited. The PPV for PJI in general was 82%,
using a cutoff value of 50 mg/L, it shows excellent potential which is lower than when using other available biomark-
to diagnose a PJI. More importantly, with a NPV of 97%, ers.18 Patients with synovial inflammation due to other
it is a promising marker to exclude PJI in patients with a causes than an infection may also have high synovial cal-
clinical suspicion of a chronic PJI, and shows promise for protectin levels, as has been outlined in our results. Syno-
use in daily clinical practice. vial calprotectin has been used as a biomarker for the
Calprotectin was measured in the laboratory in this activity of disease, therapeutic response and prognosis in
study, but it can relatively easily be measured in the clinic or patients with rheumatoid arthritis. Abildtrup et al10
operating theatre. We used a centrifuge before subjecting showed in a recent meta-analysis, that the mean synovial
the synovial fluid to the lateral flow assay. This could be level of calprotectin in patients with rheumatoid arthritis is
addressed in future studies. An important advantage of the 110 mg/L. Therefore, this should be borne in mind when
use of calprotectin is the low cost. Apart from the purchase using the level of calprotectin to diagnose a PJI in a patient
of the calprotectin quantity reader, measuring the level of with rheumatoid arthritis. However, the number of patients
synovial calprotectin costs about 20 per sample. Also, this with rheumatoid arthritis in our study was too low to draw
test is available as a diagnostic test for bowel disease in any conclusions about the ideal cutoff value for diagnosing
most hospitals and thus easy to implement in routine care. a PJI. Nonetheless, none of the patients with a false positive
In particular, the high NPV of its measurement may have result in our study had rheumatoid arthritis.
several clinical benefits. By using a test with a high NPV, a In conclusion, our data suggest that the level of synovial
PJI can be rapidly ruled out in the clinic or emergency room calprotectin may be used as a biomarker to exclude a PJI. It
in patients who present with pain at the site of an arthro- is important to note that the Quantum Blue calprotectin
plasty. Ultimately, a negative test can be used pre-opera- test was used off-label in this study, as the measurement is
tively or in the operating theatre to rule out an infection in currently only validated for faecal calprotectin and further
patients with loosening of the arthroplasty. confirmation would be needed before using it clinically in
Because this is a pilot study, it has limitations. The num- this way.
bers of patients with a PJI in the study were small and more
data are needed on chronic infections and/or infections Take home message:
caused by microorganisms with a low virulence. In addi- - Synovial calprotectin is a potential biomarker that can be eas-
tion, cutoff values need to be determined for patients with ily implemented in the diagnostic algorithm for patients with a
clinical supsicion of a chronic PJI.
rheumatoid arthritis and the influence of antibiotic and
-With its high specificity and negative predictive value, synovial calprotec-
immunosuppressive treatment on the levels of synovial cal-
tin may be used to exclude a PJI.
protectin needs to be determined. Based on our limited
data, caution should be taken in the interpretation of a neg- Author contributions:
M. Wouthuyzen-Bakker: Study design, Data collection, Interpretation of data,
ative result in patients who are on immunosuppressive Writing the paper.
treatment, as was illustrated by the false negative test in one J. J.W. Ploegmakers: Study design, Inclusion of patients.
G. A. Kampinga: Interpretation of data.
of the patients on prednisone in our study. Secondly, the test L. Wagenmakers-Huizenga: Measurement of synovial calprotectin.
may show a false negative result in very low-grade infec- P. C. Jutte: Study design, Inclusion of patients, Interpretation of data.
A. C. Muller Kobold: Study design, Quality assessment laboratory measure-
tions as illustrated by the patient with a Propionibacterium ments synovial calprotectin, Writing material and methods section on the
acnes infection. Frangiamore et al17 showed a sensitivity of measurement of synovial calprotectin.

only 63% for alpha-defensin in patients with a PJI of the 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.
shoulder, when infection was caused by Propionibacterium
acnes in nine of 14 patients. This article was primary edited J. Scott.

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