The value of synovial biopsy, joint
aspiration and C-reactive protein in the
diagnosis of late peri-prosthetic infection
of total knee replacements
B. Fink, C. Makowiak, M. Fuerst, I. Berger, P. Schäfer, L. Frommelt
From Orthopaedic Clinic Markgröningen, Markgröningen, Germany
? B. Fink, MD, Professor, Orthopaedic Surgeon
? C. Makowiak, MD, Resident
Department of Joint Replacement, General and Rheumatic Orthopaedics
Orthopaedic Clinic, Markgröningen, Kurt-Lindemann-Weg 10, 71706 Markgröningen, Germany.
? M. Fuerst, MD, Orthopaedic Surgeon
Rheumaklinik Bad Bramstedt, University of Hamburg-Eppendorf, Oskar-Alexander-Strasse 26,
24576 Bad Bramstedt, Germany.
? I. Berger, MD, Professor, Pathologist
Institute of Pathology
Klinikum Kassel, Mönchebergstrasse 41-43, 34125 Kassel, Germany.
? P. Schäfer, MD, Microbiologist
Joint Practice of Laboratory Medicine Ludwigsburg, Wernerstrasse 33, 71636 Ludwigsburg,
? L. Frommelt, MD, Microbiologist
Service of Infectious Diseases, Clinical Microbiology and Infection Control
ENDO-Klinik, Holstenstrasse 2, 22767 Hamburg, Germany.
Correspondence should be sent to Professor B. Fink; e-mail: email@example.com
©2006 British Editorial Society of Bone and Joint Surgery
doi:10.1302/0301-620X.90B7.20417 $2.00 J Bone Joint Surg [Br] 2008;90-B: Received 1 November
2007;Accepted after revision 22 February 2008
We analysed the serum C-reactive protein level, synovial fluid
obtained from joint aspiration, and synovial biopsies of 145
knee replacements prior to revision to assess the value of these
parameters in diagnosing late infection. Five further synovial
biopsies were used for histological analysis. Samples were also
obtained during the revision and incubated and analysed in an
identical manner for 14 days.
A total of 40 total knee replacements were found to be
infected (prevalence 27.6%). The aspiration technique had a
sensitivity of 72.5% (SD 13.8, 95% CI), a specificity of 95.2% (SD
4, 95% CI), a positive predictive value of 85.3% (SD 11.9, 95%
CI), a negative predictive value of 90.1% (SD 5.6, 95% CI) and
an accuracy of 89%. The biopsy technique had a sensitivity of
100% (SD 0, 95% CI), a specificity of 98.1% (SD 2.6, 95% CI), a
positive predictive value of 95.2% (SD 6.4, 95% CI), a negative
predictive value of 100% (SD 0, 95% CI) and an accuracy of
98.6%. C-reactive protein with a cut-off-point of 13.5 mg/l had
a sensitivity of 72.5% (SD 13.8, 95% CI), a specificity of 80.9%
(SD 7.5, 95% CI), a positive predictive value of 59.2% (SD 13.8,
95% CI), a negative predictive value of 88.5% (SD 7.5, 95% CI)
and an accuracy of 78.1%.
We found that biopsy was superior to joint aspiration and C-
reactive protein in the diagnosis of late peri-prosthetic infection
of total knee replacements.
The incidence of peri-prosthetic infection following total
knee replacement (TKR) ranges from 1.1% to 12.4%,
and in some reports it is reported to be the most frequent
cause of failure during the first five years after implanta-
tion.1-4 Therefore, diagnostic accuracy of post-operative
infection is paramount in patients with a painful and
Whereas early infections (four weeks after implanta-
tion) usually cause a local and systemic inflammatory
response, this is often missing in cases of late infection
making the diagnosis difficult. Moreover, the classic
clinical signs, laboratory tests, radiographs and bone
scans are associated with a high level of false positives
and negatives.7 Precise identification of bacteria and
their antibiotic resistance patterns is helpful in planning
treatment prior to surgery, and also provides the surgeon
with an opportunity to add bacteria-specific antibiotics
to the bone cement.8 Therefore, aspiration of the joint
for bacteriological analysis of the synovial fluid is car-
ried out routinely. However, the value of this investiga-
tion remains controversial. Sensitivity is reported to vary
from 12% to 100% and specificity from 81% to 100%
(Table I).9-19 This poor accuracay has been attributed to
contamination of the aspirated fluid, bacteria that are
difficult to grow in culture, such as facultative anaerobes
and Gram-negative organisms, or to non-withdrawal of
antibiotic therapy prior to aspiration.9,10,20,21
In an earlier study of 86 revision TKRs, we showed
that pre-operative synovial biopsy was superior to joint
aspiration for the diagnosis of peri-prosthetic infec-
tion.12 Aspiration had a sensitivity of 68.8%, a specific-
ity of 96.6%, a positive predictive value of 84.5% and a
negative predictive value of 92.2%. Synovial biopsy, on
the other hand, had a sensitivity of 100%, a specificity
of 94.7%, a positive predictive value of 87.4% and a
negative predictive value of 100%. However, this partic-
ular study had a methodological flaw in that both the
diagnostic methods were performed in only 15 TKRs.12
The objectives of the present study, therefore, were to
carry out a new prospective examination of both the
diagnostic procedures using a larger patient population,
and to investigate the hypothesis that synovial biopsy
was superior to joint aspiration and C-reactive protein
for the diagnosis of late peri-prosthetic infection after
Patients and Methods
Between July 2004 and September 2007, 144 patients
(145 knees) who needed a revision TKR for component
loosening were prospectively included into the study fol-
lowing appropriate consent. The study was approved by
the Local Ethics Committee prior to commencement.
Prosthetic loosening was defined as proposed by Math et
al22 and radiographs were analysed according to the
Knee Society Scoring system.23 All the patients under-
went diagnostic aspiration and synovial biopsy of the
knee prior to revision. Of the 144 patients only eight
showed local signs of infection with an accompanying
fistula. The mean age of the patients was 68.4 years (SD
9.9) and 81 were female. The primary diagnosis was
osteoarthritis in 128 cases (89%) and rheumatoid
arthritis in 16 (11%). The aspiration and biopsy were
carried out a mean of 38.2 months (2 months to 21
years) after the primary implantation.
Values of C-reactive protein (CRP) were also deter-
mined before the operation. None of the patients were
on any antibiotics for four weeks prior to aspiration and
biopsy, as recommended by Burnett et al,24 Mont,
Walden and Hungerford,25 Lonner et al26 and Gollwit-
zer et al,27 to minimise the risk of antibiotic-induced
false-negative results. In the eight patients with fistulae,
antibiotic treatment was withdrawn and the patients
were examined at weekly intervals up to the date of the
Aspiration and biopsy were carried out under aseptic
conditions in the operating theatre under general anaes-
thesia without a tourniquet. The synovial fluid was col-
lected in vials containing BD BACTEC-PEDS-PLUS/F
Medium (Becton Dickinson, Heidelberg, Germany).
This medium was originally designed to optimise blood
cultures from children, and had proved superior to stan-
dard blood culture media in both recovery and time to
detection of clinically significant microorganisms, even
in low-volume samples.28 The biopses were obtained
using arthroscopic biopsy forceps introduced via an
anterolateral approach. The samples were obtained
from five different areas of the knee joint, close to the
components. The biopsies for bacteriological analysis
were obtained blind, without filling the joint with fluid,
to avoid any dilution of infecting organisms. The knee
was subsequently assessed arthroscopically for any
bleeding and damage to the components caused by the
biopsy forceps and, at the same time, five non-blind tis-
sue samples were obtained for histological examination.
A single dose of 2 g cefazoline (i.v) was given as prophy-
laxis once all samples had been obtained.
The biopsy samples were placed in sterile tubes and
transferred together with the aspirated fluid to the
microbiology laboratory within an hour of sampling.
Specimens were processed immediately upon arrival.
PEDS culture vials were treated with fastidious organ-
ism supplement (Becton Dickinson), a growth enhancer
which improves cultivation of fastidious organisms from
normally sterile body fluids other than blood, according
to the manufacturer’s instructions, and incubated using
the BD BACTEC 9050 automatic blood culture system
(Becton Dickinson). Cultures were discontinued and
declared negative if there was no growth after 14
days.18,27,29,30 Cultivation of tissue samples was carried
out as described in previous studies.7,18,27,29,31,32
The results of each series of tests (aspiration, bacteri-
ology and histology, and serum CRP level) were evalu-
ated individually. A joint
bacteriologically positive if the same bacterium was
identified in at least two samples.33 A joint was consid-
ered to be histologically positive if at least five neutro-
philic polymorph leucocytes per high-power field (×
400) were identified in ten such fields.32,34-37 A CRP
value > 13.5 mg/l was regarded as positive.38
was regarded as
Based on the combined histology and microbiology
results, a joint was considered to be infected if at least
one of the following conditions was fulfilled:7,31,32 dem-
onstration of the same micro-organism in at least two of
the cultures; or demonstration of a micro-organism in at
least one sample and at least five neutrophilic poly-
morph leucocytes per high-power field (× 400) in the
associated histological preparation. The growth of a
microorganism in only one culture medium without any
histological signs of infection was regarded as a contam-
During revision, samples were obtained again from
five different areas close to the components and were
incubated for 14 days, as above. In addition, the syn-
ovium and peri-prosthetic connective tissue were
obtained for histological assessment. Peri-operative anti-
biotics were administered only after all the samples had
been obtained. At least ten high-power fields (× 400) per
synovium and peri-prosthetic tissue biopsy were analy-
sed for neutrophilic polymorph leucocytes. The same
criteri were used for the diagnosis of infection.
The diagnosis obtained from the revision surgery sam-
ples was regarded as the definitive result with respect to
peri-prosthetic infection, and was used to evaluate the
diagnostic methods (joint aspiration, biopsy and CRP).
The sensitivity, specificity and the positive and nega-
tive predictive values of each diagnostic method (aspira-
tion, microbiological examination,
examination, CRP and microbiological and histological
examination in combination for the biopsy method)
were determined. Bayes’ equation was used to calculate
these values.39 The accuracy of the techniques was cal-
culated from the sum of the true positives and the true
negatives divided by the number of tests carried out. All
calculations were carried out using SPSS for Windows,
version 10.0 (SPSS Inc., Chicago, Illinois). A p-value <
0.05 was considered to be statistically significant.
Of the 145 revision TKRs 40 were classified as infected,
giving a prevalence of 27.6%. This is relatively high, but
as our hospital is the reference centre for prosthetic joint
infection, it attracts higher numbers of such cases. The
micro-organisms identified are shown in Table II.
Patients with a peri-prosthetic infection had signifi-
cantly higher values of CRP, with a mean of 50.63 mg/l
(SD 10.23) than those who did not have an infection,
with a mean of 14.91 mg/l (SD 3.24) (p = 0.002). A total
of 29 patients from the infected group had a CRP ≥ 13.5
mg/l. However, 20 patients from the non-infected group
had a CRP ≥ 13.5 mg/l, and 85 had a CRP < 13.5 mg/l.
The diagnostic value of the CRP and the sensitivity, spec-
ificity, predictive values and accuracy of the various
investigations are shown in Table III.
At a prevalence of 27.6% for infected TKRs in this
study, the probability that a biopsy with a positive result
really is infected amounts to 95.2% (SD 6.4, 95% confi-
dence intervals (CI), positive predictive value). The
probability that a biopsy with a negative test result is
actually not infected is 100% (SD 0%, 95% CI negative
predictive value). The accuracy is 98.6%. Therefore,
biopsy as a combination of the bacteriological and his-
tological examination showed the highest diagnostic
value for identification of late peri-prosthetic infection.
During the arthroscopic examination of the knee that
followed the biopsy there was no observable damage,
such as scratches, to the components, nor any bleeding
that required haemostasis. There were no instances
where an additional anteromedial portal was required.
No other complications occurred during this study; in
particular, there were no infections or wound healing
problems associated with the additional anterolateral
The 40 infected TKRs subsequently underwent revi-
sion surgery whereby bacterium-specific antibiotics
were added to the bone cement and bacterium-specific
systemic antibiotic therapy was initiated. During the
subsequent follow-up period of 23.4 months (SD 14.9),
only one patient had a recurrent infection.
A pre-operative bacteriological examination should be
performed prior to revision of a loose or painful TKR.
Several methods of diagnosing infection have been
described. The serum level of CRP is regarded as an
important diagnostic parameter and has a sensitivity of
91%, a specificity of 86%, a positive predictive value of
74%, a negative predictive value of 95% and an accu-
racy of 88%.38 However, although we found signifi-
cantly higher levels of CRP in the group with peri-
prosthetic infections, the predictive power of the CRP in
our study was not as good as that reported by oth-
ers.38,40 A possible explanation may be that 16 patients
with rheumatoid arthritis were included in our study
and therefore had increased baseline CRP levels because
of the nature of their disease. Only one patient with
rheumatoid arthritis had an infected TKR. Moreover,
the cut-off point for the value of CRP associated with an
infection is probably influenced by the distribution of
the individual values in any one cohort, so that different
patient cohorts will exhibit different cut-off points. This
might explain the different levels of significance
attached to CRP as a diagnostic tool in the literature.7,27
A further disadvantage of CRP is that it does not identify
the micro-organism in question and therefore does not
provide the information necessary to develop a specific
therapeutic antibiotic regimen.8,18,30 On the other hand,
aspiration of the joint offers this advantage. Therefore,
many authors recommend routine aspiration before a
revision, even when there is no indication of an infec-
tion, because of its high diagnostic value.21,41-43
Our results support the hypothesis that synovial
biopsy is superior to aspiration in the diagnosis of late
peri-prosthetic infection. In particular, the sensitivity
and the negative predictive value of biopsy were 100%
in the present and our pilot study, and infection can be
reliably ruled out with this method. We had no infec-
tions or other complications, although individual cases
have been previously described.44
The length of the incubation period is important for
identifying the micro-organism in aspirated fluid or
biopsies because bacteria that lead to a peri-prosthetic
infection exist in low numbers in the biofilm and are
often in a sessile form which grows slowly.24,45,46 We
chose to incubate our specimens for 14 days, based on
previous studies.18,27,29,30 An inappropriate incubation
period may be the reason for the poor sensitivity of tests
as reported in previous studies.14,16 Moreover, patients
should not be treated with antibiotics prior to the test. If
this is not the case, then at least 14 days, and if possible
four weeks, should elapse before any sampling occurs.9-
11,24,25 However, if the patient develops symptoms of
systemic infection during the antibiotic-free period, the
TKR should be revised without delay. In these cases, an
antibiotic-loaded spacer should be used in addition to
broad-spectrum antibiotic therapy.24
One potential weakness of our study was that the
biopsy was carried out in a blinded fashion with biopsy
forceps, without filling the knee joint with fluid. The
potential for damage to the surface of the components is
a disadvantage of this technique. However, our study
only addressed the patients with loose components,
where revision surgery was indicated, and therefore any
iatrogenic damage to the prostheses during the biopsy
was of lesser importance. We do not recommend this
technique for the diagnosis of peri-prosthetic infection
in a well-fixed TKR. In addition, future studies should
focus on examining data obtained via a blind biopsy
compared with those obtained via a biopsy carried out
by arthroscopic visualisation.
Tissue samples were also sent for histological exami-
nation. We found a sensitivity of 90% and a specificity
of 95% with histology in our study, although some
authors have reported these values to be approaching
Our study shows that biopsy is superior to aspiration
of the joint as a pre-operative diagnostic method in its
ability to confirm or rule out the presence of late peri-
prosthetic infection. It also offers the advantage of com-
bining both bacteriological and histological examina-
It is a minor procedure without major complications,
with a high accuracy, and we use it routinely as a diag-
nostic procedure for peri-prosthetic infection in patients
with TKRs. However, in patients with stable implants,
where peri-prosthetic infection has to be ruled out, we
recommend aspiration of the joint. Only in patients with
a negative aspiration but an increased CRP or clinical
signs of infection, would we recommend a biopsy.
Whether a blind technique gives better results that the
arthroscopically-assisted method remains to be seen.
No benefits in any form have been received or will be received from a commercial party
related directly or indirectly to the subject of this article.
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Table I. Value of joint aspiration in the diagnosis of the infected total knee replacement
Barrack et al10
Duff et al11
Fuerst et al12
Glithero et al13
Kordelle et al14
Johnson et al15
Levitsky et al9
Morrey et al16
Panousis et al17
Teller et al19
Virolainen et al7
* without previous antibiotic therapy
† knee and hip total replacement
‡ all infected
§ only hip total replacement
Positive predictive value
Negative predictive value
Table II. Micro-organisms identified in the 40 cases of peri-prosthetic infection
and their frequency of detection (one case with identification of Staphylococcus
aureus and Peptostreptococcus species)
Streptococcus dysgal ssp. equisimilis
Number of infected joints
Table III. Numbers of true positive, true negative, false positive and false negative examinations for the different diagnostic methods, as well as sensitivity, specificity,
positive predictive value, negative predictive value and accuracy of these diagnostic tools
Sensitivity (SD 95% confidence intervals) (%)
Specificity (SD 95% confidence intervals) (%)
Positive predictive value (SD 95% confidence intervals)
Negative predictive value (SD 95% confidence intervals)
Page 1 95% CI: AQ - Please explain you state 95% CI but do not give the values.
Page 2 86: AQ - 75 in Table I. Please be consistent.
Page 268.8%: AQ - 69 in Table I. Please be consistent.
Page 296.6%: AQ - 97 in Table I. Please be consistent.
Page 284.5%: AQ - 85 in Table I. Please be consistent.
Page 2 92.2%: AQ - 92 in Table I. Please be consistent.
Page 2 sd 9.9: AQ - Please give range.
patients or knees. Amend as necessary.
128: AQ - 128 + 16 = 144 not 145 cases. Please be clear if you are discussing
Page 3 PEDS: AQ - Please spell out.
the first revision?
revision: AQ - Were antibiotics given in the time period between the biopsy and
Page 4p-value: AQ - Is this correct?
Page 4 p = 0.002: AQ - Please name the statistical test used.
this. Why have you stated 95% CI but not given the 95% CI values?
95% confidence intervals (CI), positive predictive value: AQ - Please explain
ed 95% CI but not given the 95% CI values?
95% CI negative predictive value: AQ - Please explain this. Why have you stat-
Page 5 sd 14.9: AQ - Please give range.
Page 5study: AQ - Is this reference 13? If not, please give reference.
Page 6 No benefits: AQ - Is this statement correct?
Page 9 1: AQ - Which species?
95% confidence intervals: AQ - Please explain you state 95% CI but do not give
95% confidence intervals: AQ - Please explain you state 95% CI but do not give
95% confidence intervals: AQ - Please explain you state 95% CI but do not give a val-
95% confidence intervals: AQ - Please explain you state 95% CI but do not give a val-