Le Infezioni in Medicina, n.

1, 6-10, 2020

6 REVIEWS

Serum procalcitonin as an adjunct

in diagnosing prosthetic joint
infection in total knee replacement
and total hip replacement
Fransiska Dhyana Guerreiro1, Aadil Mumith2, Kordo Saeed3
1
Queen Alexandra Hospital, Portsmouth Hospitals Trust, Portsmouth, England, United Kingdom;
2
Royal Hampshire County Hospital, Hampshire Hospital NHS Foundation Trust, Winchester, England,
United Kingdom;
3
University Hospital Southampton NHS Foundation Trust and University of Southampton, England,
United Kingdom

SUMMARY
There are still many unknowns regarding the potential
application of Procalcitonin (PCT) as an adjunct to aid
the diagnosis of Prosthetic Joint Infection. A systemat-
ic review searching scientific articles was performed
with keywords “Procalcitonin”, “Total Hip Replace-
ment”, and “Total Knee Replacement” (n=123). After
review of the abstract and full text for relevance, ten
articles were included (n=10). Serum PCT levels for
chronic Total Hip Replacement (THR) and Total Knee
Replacement (TKR) have a range of mean values from
1.5 ng/ml to 14.2 ng/ml. Specificity ranges from 0.27
to 0.98, while sensitivity is from 0.33 to 0.9. On pri-
mary THR/TKR with confirmation of non-infected
status, serum PCT peaks between 1-3 days post-op-
eratively, with peak levels varying from 0.12-0.79 ng/
ml. Based on this review, serum PCT is not a good
adjunct in diagnosing Prosthetic Joint Infection (PJI).
Synovial fluid PCT fluid may add better clinical sup-
port but requires further studies. There were several
limitations with this review: the studies are small and
heterogeneous, there was a variable definition of PJI,
and there was a wide range of mean values, sensitivity
and specificity.
Keywords: periprosthetic joint infection, procalcitonin,
total hip replacement, total knee replacement.

n INTRODUCTION tonin to be one of the measurable biomarkers of

infection [1].

P rocalcitonin (PCT) is the precursor of calci-

tonin. Composed of 116 amino acids, it is pro-
duced via transcription of CALC-1 gene by C cells
of thyroid gland in healthy and non-infected in-
dividuals (Figure 1). In the presence of infection,
non-neuroendocrine cells can produce procalci-
tonin, thereby markedly increased the concentra-
tion in the body. This rise has allowed procalci-
Corresponding author
Fransiska Guerreiro
E-mail: fransiskaguerreiro@outlook.com
Some studies suggest that serum PCT is a useful
adjunct for management of bacterial infection
such as in sepsis, pneumonia, bacteraemia, uri-
nary tract infection, and reducing antibiotic expo-
sure [1-8].
Despite many controversies, C Reactive Protein
and ESR are commonly used as serum biomarkers
to assist in the diagnosis of Prosthetic Joint Infec-
tions (PJI) [9]. In the early post-operative periods
the inflammatory markers routinely used to de-
tect infection could be elevated from the effect of
the surgery itself. Furthermore, normal values of
these inflammatory markers do not rule out PJI
 Serum procalcitonin as an adjunct in diagnosing prosthetic joint infection 7

Figure 1 - Structure of procalcitonin.

Figure 1 - Structure of procalcitonin.

[10]. CRP level, for example, could be normal on PJI. This paper only includes original research stud-
PJI with organism of low virulence [11]. Having ies on Total Hip Replacement and Total Knee Re-
alternative biomarkers specific to infection itself placements, published in English. This is because
would help clinicians to detect early PJI. these lower limb arthroplasties are more common
PJI carries high mortality and morbidity. Treat- than other groups but also has a major impact on
ment ranges from long term suppressive antibi- patient quality of life, e.g., mobility, when compli-
otics to DAIR (Debridement, Antibiotics, and Im- cation developed.
plant Retention), and revision arthroplasty. There Database used for the study are Ovid, Google
is a level of ambiguity on diagnostic criteria on PJI scholar, and Medline with the key words “Pro-
as per the Musculoskeletal Infection Society and
Infection Disease Society of America.
Serological tests adjuncts for diagnosing PJI is
desirable. A serum blood test is minimally-inva-
sive, has less cost associated with the procedure
and minimal risk of introducing microbes into the
prosthesis. Indeed, the 2018 International Con-
sensus Meeting on MSK Infection has put this as
one of the research priorities [12].
This paper systematically reviews studies on the
use of procalcitonin as a biomarker for PJI on pa-
tients receiving Total Hip Replacement (THR) and
Total Knee Replacement (TKR).

n METHODS
The authors performed a systematic search on
Pubmed, GoogleScholar and Ovid for original re-
search paper on the use of procalcitonin to detect Figure 2 - Diagram of the systematic review.

Figure 2 - Diagram of the systematic review.

8 F.D. Guerreiro, A. Mumith, K. Saeed

calcitonin”, “Total Hip Replacement”, and “Total n DISCUSSION

Knee Replacement”. Inclusion criteria are original
research articles, serum procalcitonin, and stud-
ies on THR and TKR. No date/year limit was ap-
plied. Date of search was from inception to De-
cember 29th, 2018.
n RESULTS
Databases search yield 121 articles. After abstract
and title screening, 105 were excluded leaving 16
full text articles retrieved. Six were further ex-
cluded for not a total hip/knee specific, review
articles, and not measuring serum procalcitonin.
Ten articles meeting the inclusion criteria were re-
viewed. The data contained within these articles
then divided into two groups, confirmed PJI and
non-infected arthroplasty. They are illustrated in
Table 1 and Table 2 below.
PCT for chronic THR and TKR has a mean value
from 1.5 ng/mL to 14.2 ng/mL. Specificity range
from 0.27 to 0.98, while sensitivity is from 0.33 to
0.9. On primary THR/TKR with confirmation of
non-infected status, PCT peaks between 1-3 days
postoperatively, with peak levels vary from 0.12-
0.79 ng/mL.
Diagnosis and management of biofilm associated
PJI remains challenging. Diagnosis is especially
difficult on organisms that are not virulent enough
to incite a host response. Traditional microbiology
culture can be unreliable when detecting bacteria
in biofilms. Serological tests, although are part of
first line investigation, cannot be used solely to di-
agnose PJI [12-23].
This systematic review suggests that there is cur-
rently limited evidence to support the use of se-
rum PCT as an adjunct to differentiate PJI to asep-
tic loosening. The articles that were included in
this review show a level of heterogeneity. These
are both shown in the infected and non-infected
groups.
On the confirmed PJI group, the studies from Gh-
ler et al. 2013, Ettinger et al. 2015, and Bottner et
al. 2009 have the most complete data. Although
Ghler et al. 2013 and Ettinger et al 2015 demon-
strated high level of sensitivity at 0.9 with poor
specificity at 0.33 and 0.27 respectively, this was
contradicted by Bottner et al. 2009 with the re-
verse of poor sensitivity 0.33 and high specificity
at 0.98. Each of these three studies used different

Table 1 - Serum Procalcitonin on Infected Total Hip Replacement and Total Knee Replacement.
PCT Positive Negative
PCT Cut Off
Author n Diagnosis mean Sensitivity Specificity Predictive Predictive
Range (ng/mL)
(ng/L) Value Value
Revision THR
Bottner and TKR with
et al. 2007 21 positive culture and 1.5 0-12.6 <0.3 0.33 0.98 0.87 0.8
(13) histological evidence
of deep infection
Glehr
Revision for infected Not Not Not Not
et al. 2013 84 <0.35 0.9 0.33
THR and TKR available available available available
(14)
Ettinger Revision THR,
et al. 2015 20 TKR and TSR for low 0.04 0.03-0.07 <0.25 0.9 0.27 0.25 0.9
(15) grade infection
Falzarano Chronic Infected
Not Not Not Not Not Not
et al. 2017 5 THR (5 weeks 2.8
available available available available available available
(16) to 23 months)
Falzarano Haematogenous
Not Not Not Not Not Not
et al. 16 infected THR 14.2
available available available available available available
2017(16) (more than 24 months)
Drago
Revision for THR Not Not Not Not Not Not
et al. 2011 20 0.3
failure due to infection available available available available available available
(17)
 Serum procalcitonin as an adjunct in diagnosing prosthetic joint infection 9

Table 2 - Serum Procalcitonin on non-infected arthroplasty group.

Author Rationale Type n Findings Limitation
Investigating the physiological Values at follow up
Battistelli PCT level peaks
pattern of PCT on the first month Prospective blood test described
et al. 2014 51 at day 1 post op (mean
of uncomplicated primary THR observational as ‘increased fold
(18) 0.12 ng/mL
(Day 0,1,3,7,14,30) to basal value’
Investigating the physiological
Bouaicha PCT level peaks
pattern of PCT on the first 5 days Prospective Patients followed up
et al. 2013 31 at day 2 post op (mean
of uncomplicated primary THR observational to 6 weeks
(19) 0.28 ng/mL)
(Day 0,1,2,3,4,5)
Zhao Investigating the physiological PCT level peaks at day 1
Prospective
et al. 2017 pattern of PCT on the first 10 days 36 post op (mean 0.23 ng/ No follow up
observational
(20) of primary THR (Day 0,1,4,7,10) mL)
The PCT concentrations
Complications
Múgica Investigating PCT pattern 0.5 ng/mL corresponded
Prospective referred are medical
et al. 2011 on patients undergoing primary 128 with the appearance of
observational and superficial site
(21) TKR (Day 0,1,2,3) clinical complications in
infection/necrosis
75% of the cases
Ali Investigating PCT pattern on PCT level peaks
Prospective Patients followed up
et al. 2009 patients undergoing primary THR 59 at day 3 post op (mean
observational to 6 weeks
(22) and TKR (Day 0,1,3,5) 0.79 ng/mL)
PCT level on
Ettinger Investigating PCT values on The timing of
Prospective aseptic loosening
et al. 2015 revision THR and TKR for aseptic 57 blood test was not
observational is significantly lower than
(15) loosening based on MSIS criteria mentioned
septic group (p<0.5)
Comparing PCT values on Revision PCT level is significantly
Bottner of THR and TKR for aseptic higher on septic
Prospective
et al. 2007 loosening vs septic arthroplasty. 57 arthroplasty group No follow up
observational
(13) Patients grouped based on compared to aseptic
intraoperative culture and histology loosening (p=0.003)

cut off points for their findings, adding into the
heterogeneity.
The other authors on the confirmed PJI group
have published their mean PCT findings. Their
mean values, once again, show heterogeneity.
Mean values range from 0.04 to 14.2. With such
a wide range of mean values, it is difficult to pro-
pose that serum PCT can be useful as an adjunct
to aid the diagnosis of PJI presence.
Bottner et al. 2007 study shows a statistically
significant difference between aseptic loosening
compared to PJI. However, this was a small-scale
study and included systemic inflammatory con-
ditions in their patient population.
Early works from small-scale synovial studies
for procalcitonin in diagnosing PJI however, is
promising. Saeed et al. 2013 non-interventional,
non-blinded study compares synovial fluid PCT
between infected (PJI and Native septic arthritis)
and non-infected (aseptic loosening, crystal ar-
thropathy, osteoarthritis, and other inflammato-
ry arthritis) [24]. This group found a statistically
significant difference between the mean synovial
PCT of two groups.
A similar result is suggested by Sa-Ngasoongsong
et al. 2018 [25]. Their prospective cohort study
compares the synovial fluid PCT values between
the infected and non-infected groups of patients
undergoing hip and knee revision arthroplasty.
They found a statistically significant difference in
the synovial PCT values.
The use of synovial fluid biomarkers as an adjunct
is evolving currently. Alpha defensin is one of the
most promising [10, 26, 27]. Serum biomarkers,
on the other hand, show variability in its reliabil-
ity. Normal CRP does not rule out PJI. High CRP
could be caused by co-existing infections, inflam-
mation, or infection with organisms of low viru-
lence [10, 11, 28]. Synovial based analysis could be
the future in PJI diagnosis.
10 F.D. Guerreiro, A. Mumith, K. Saeed
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