Journal of Orthopaedic Science xxx (xxxx) xxx

Contents lists available at ScienceDirect

Journal of Orthopaedic Sciencejournal homepage: http://www.elsevier.com/locate/jos

Original Article

Can serum C-reactive protein determine the timing of reimplantationin two-stage revised arthroplasty for periprosthetic hip infection?
Kenichi Oe*, Hirokazu Iida, Ryo Inokuchi, Yosuke Otsuki, Takashi Toyoda,
Fumito Kobayashi, Shohei Sogawa, Tomohisa Nakamura, Takanori Saito
Department of Orthopaedic Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 573-1010, Japana r t i c l e i n f o

a b s t r a c t

Article history:
Received 20 April 2023
Received in revised form
10 July 2023
Accepted 14 July 2023
Available online xxx

Background: There are no deﬁnitive guides to determine the timing of reimplantation in two-stage
revision total hip arthroplasties (THA) for periprosthetic joint infection (PJI). This study was to design
to support a rational strategy of surgical treatment using serum C-reactive protein (CRP).
Methods: We analyzed a total of 75 hips for PJI in the process of performing two-stage and multiplestage revision THAs. CRP level was retrospectively evaluated every week and transformed to log2
(CRP) using a logistic regression model. Prosthesis survival from recurrent infection was determined by
Kaplan-Meier analysis, using implant removal as the endpoint. Receiver operating characteristic curves
were calculated using each log2 (CRP) to assess predictions of recurrent infection.
Results: The 10-year survival rates were 85% (95% conﬁdence interval, 76e95) and 100% for two-stage
and multiple-stage revision THAs, respectively. Preoperatively, at 1, 2, 3, and 5 weeks, log2 (CRP) was
not associated with recurrent infection. In failed two-stage revision THAs, log2 (CRP) at 3 weeks divided
by that at 2 weeks showed a signiﬁcant difference. Failure was associated with a ratio of >4.0 for the CRP
level between 3 and 2 weeks.
Conclusion: In two-stage revision THA for PJI, patients with CRP elevation from 2 weeks to 3 weeks,
especially 4-fold elevation, suggests the need for further debridement and postponement of secondstaged reimplantation.
© 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

Keywords:
C-reactive protein
Infection
Log2
Total hip arthroplasty
Two-stage revision

1. Introduction
In total hip arthroplasty (THA), the incidence of prosthetic joint
infection (PJI) requiring revision surgery has seen a notable rise
globally, and the management of PJI presents major challenges[1,2]. The two primary options involve treatment with or without
implant removal. Without removal, the indications and outcomesremain controversial. Therefore, the treatment for PJI is generally
revision THA with implant removal, either as a one-stage or a twostage procedure. One-stage revision THA is often preferred inEurope, while in the rest of the world, two-stage revision THA isconsidered the gold standard treatment for PJI [3,4]. Advantages of
one-stage revision THA include shorter hospitalization, shorter
duration of antibiotic treatment, lower mortality, lower rate ofcomplications, and lower overall healthcare costs [5,6]. Two-stage* Corresponding author.
E-mail address: oeken@hirakata.kmu.ac.jp (K. Oe).

revision THA is generally considered safe and secure, but includes
the disadvantages of a second operation, higher costs, longer
treatment periods, and greater economic burden [7,8]. Additionally,in a planned two-stage revision THA, debridement must be
repeated if the infection was not controlled at the initial stage ofsurgery. The resulting procedure is called “multiple-stage revision
THA” [9]. However, no deﬁnitive guides are available to determine
the timing of reimplantation, and it is difﬁcult to decide whether
THA should be performed in the second stage of surgery during
two-stage revision [10e15].
Serum C-reactive protein (CRP) is inexpensive, readily available,
and the most popular marker for detecting PJI. Elevated CRP level ismore accurate than other serum parameters and is included in the
diagnostic criteria from the Musculoskeletal Infection Society(MSIS) [16e19]. However, some studies have suggested that thenormalization of CRP was not associated with infection-free survivorship, especially for infected total knee arthroplasty (TKA)[20e22]. Particularly, the determination of CRP levels after the
initial stage of surgery in two-stage revision THA remains equivocal

https://doi.org/10.1016/j.jos.2023.07.005
0949-2658/© 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

Please cite this article as: K. Oe, H. Iida, R. Inokuchi et al., Can serum C-reactive protein determine the timing of reimplantation in two-stage
revised arthroplasty for periprosthetic hip infection?, Journal of Orthopaedic Science, https://doi.org/10.1016/j.jos.2023.07.005

K. Oe, H. Iida, R. Inokuchi et al.

Journal of Orthopaedic Science xxx (xxxx) xxx

acrylic cement (ALAC) for each patient (Fig. 2). ALAC was prepared in accordance with the protocol by Jiranek et al. [24], using
over 3.6 g of antibiotic per 40 g of cement in the ﬁrst stage of twostage or multiple-stage revision THA. We selected antibiotics for
ALAC, based on the results for individual bacterial sensitivities frompre-operative aspiration. In Gram-positive or unknown bacterial
infections, a combination of vancomycin 3.0g and amikacin 0.6g
were generally used because of the high elution levels that such
blended antibiotics can provide [25,26]. For reimplantation, weused 1.0e2.0 g of antibiotic per 40 g (ENDURANCE Bone Cement,
DePuy International, Leeds, United Kingdom).
PJI treatment requires thorough debridement and the use of
sufﬁcient local and systemic antibiotics [9]. We employed a transgluteal approach for debridement, with complete removal of all
implant components, cement, granulation, and necrotic andinfected tissues. Routine radiographs and computed tomographyscans, along with radioisotopes if needed, were used to assess
necrotic and infected tissues and ensure thorough debridement.
Before initiating capsulotomy, we aspirated the hip joint and sent asample for microbiological analysis. Periprosthetic tissue specimens were also submitted for microbiological and pathologicaltesting. We then used hydrogen peroxide solution or povidone
iodine to thoroughly ﬂush the hip joint by pulse irrigation.
Antibiotic-impregnated beads have shown characteristically higher
elution and longer duration of antibiotic delivery than spacers, bothin vivo and in vitro, due to the greater surface area of the beads[27,28]. For each two-stage or multiple-stage revision THA, we
prepared a handmade rod and beads containing sufﬁcient highdose ALAC. After thorough debridement, we temporarily placed ahandmade rod and beads including sufﬁcient high-dose ALAC in
the debrided area. We also provided appropriate intravenous systemic antibiotic therapy for 2 weeks after the surgery. Although we
selected some antibiotics based on the results of individual bacterial sensitivities from pre-operative aspiration and intra-operative
specimens, for Gram-positive or unknown bacteria we generally
used both daptomycin and rifampicin [29]. After performing theinitial debridement, we monitored the clinical signs and CRP levels
for 6e8 weeks and then performed a second thorough debridement. If the infection had been successfully eliminated at thatpoint, we performed THA using ALAC. If the infection was not yet
fully controlled at this second stage, debridement was repeated(multiple-stage revision THA). ALAC antibiotic release was generally exhausted within 6e8 weeks [30], so whether implementing a
two-stage or a multiple-stage revision THA, we continued
debridement every 6e8 weeks until the revision was completed.

because antibiotic therapy and resected joint instability can affect
the CRP level. In the present paper, we ask, “In two-stage revision
THA for PJI, can CRP levels predict reimplantation failure?” The aimof this study was to determine the timing of reimplantation in twostage revision THA using serum CRP. We hypothesized that further
debridement and a switch to multiple-stage revision THA can beselected if the CRP level does not decrease sufﬁciently after initialdebridement.
2. Patients and methods
2.1. Study design and patients
Between January 2006 and December 2020, surgeons at our
hospital performed 119 consecutive revision THAs for PJI in 111
patients. These procedures involved one-stage revision THA in 40
hips, two-stage revision THA in 73 hips, and multiple-stage revision
THA requiring 2 debridements in 6 hips. Multiple-stage revision
THA was deﬁned as any procedure that required further debridement in the second stage of two-stage revision THA, so that theprosthesis would have to be reimplanted at a third or subsequent
stage of surgery [9]. In multiple-stage revision THA, all 6 hips werereimplanted in the third stage of surgery, with no further
debridement required. We diagnosed PJI based on the MSIS criteria[18]. A case was considered “successful” if we found no signs ofinfection at the follow-up visit >24 months after the ﬁrst revision,and as “failure” if the implant was removed as a result of recurrent
infection. We followed a total of 75 hips that involved two-stage
revision THAs, including multiple-stage revision THAs, for a meanof 5 years (range, 0.3e16 years). Patients were 19 men and 56
women. Mean age was 68 years (range, 32e86 years) at the time ofsurgery. One patient developed infection in both hips, 6 patients
relapsed and required re-replacement of the prosthesis, and 4 patients were lost to follow-up (follow-up rate, 95%) (Fig. 1). This
cohort study was approved by our institutional review board, andeach patient provided informed consent for the inclusion of patient
data in the published ﬁndings.
2.2. Surgical procedures
We generally performed two-stage revision THA in patients who
did not meet our criteria for one-stage revision THA, with the ﬁnal
decision made intraoperatively by the surgeon [9,23]. We obtained
pre-operative aspirate for each patient, determined individual
bacterial sensitivities, and custom-mixed an antibiotic-loaded

2.3. Follow-up protocol
During the waiting period for implantation, wheelchair use waspermitted on the second postoperative day following the ﬁrst
surgical procedure. Full weight-bearing was not advised until thesecond postoperative day after implantation, and patients began
walking on the 5th postoperative day. All patients received weekly
follow-up for the ﬁrst 2 months, then at 3, 6, and 9 months, andbiannually thereafter. Two orthopaedic surgeons blinded to patient
identities provided retrospective analysis. Microorganisms that had
been isolated pre- and intraoperatively were identiﬁed from patient records, and changes over time in serum CRP levels (mg/L)
were assessed.
2.4. Statistical analysis
Prosthesis survival was calculated from Kaplan-Meier analysis
with 95% conﬁdence intervals (CI), with the endpoint being theremoval of implants due to recurrent infection. For the logistic

Fig. 1. Study ﬂow chart. THA, total hip arthroplasty. PJI, periprosthetic joint infection.
2

K. Oe, H. Iida, R. Inokuchi et al.

Journal of Orthopaedic Science xxx (xxxx) xxx

Fig. 2. Radiographs of a 65-year-old female who had undergone two-stage revision total hip arthroplasty (THA): (A) before primary THA, showing dysplasia classiﬁed as Crowe
group IV, (B) primary THA with subtrochanteric shortening osteotomy, (C) ﬁve years after primary THA, showing implant loosening and subsidence, (D) antibiotic-loaded acrylic
cement beads 7 weeks after the ﬁrst-staged surgery, and (E) four years after revision THA using a cemented long stem, no recurrence.

infection control rate of 97% (73/75 hips). Microorganisms thatwere isolated preoperatively and intraoperatively are shown in
Table 2.

regression model, we transformed CRP levels to log2 (CRP) because
the values on the log scale often approximate the normal curve
reasonably well, which could allow us to calculate more reliable
odds ratio estimates. We used univariate logistic regression tomodel a linear relationship between the independent variable (X)and the probability of failure. When the expected probability of
failure at a given log2 (CRP) is p, the regression coefﬁcients represent the intercept (a) and slope (b) of this line

Table 2Isolated microorganisms: preoperative and intraoperative.

p¼ a þ bXlog
1p
We calculated receiver operating characteristic (ROC) curves,using each log2 (CRP) to assess our performance in predicting
failure. This enabled examination of the area under the curve (AUC).
All data were analyzed using one-way analysis of variance with SAS
version 9.2 (SAS Institute, Cary, NC). P value < 0.05 was consideredsigniﬁcant.

3. Results
Two-stage revision THA was successful in 61 of the 69 hips, witha 10-year implant survival rate of 85% (95% CI, 76e95). There were
no failures in multiple-stage revision THA (Table 1). For the 8 hipsthat failed two-stage revision THA, the mean duration from revised
THA to implant re-removal because of recurrent infection was 1.9
years (range, 0.3e6.2 years). Among those 8 hips, re-revision THA
was successful in 6, and for the remaining 2 hips the patient diedsubsequent to implant removal. All patients showed a ﬁnal

IsolatesTwo-stage
Success group

Two-stage
Failure group

Multiple-stage
Success group

CNS
MRSA
MSSA
MRSE
MRCNS
MSSE
Pseudomonas aeruginosa
Streptococcus sp.
Staphylococcus sp.
Peptostreptococcus sp.
Group B Streptococcus
Serratia
Enterococcus
Bacteroides sp.
Proteus vulgaris
Escherichia coli
Mycobacterium tuberculosis
FungusUnknown

19
14
9
6
3
3
1
1
2
2
3
1
1
1
0
1
1
1
17

2
2
0
0
0
0
1
0
1
1
0
0
0
0
1
0
0
0
1

1
2
0
0
1
0
0
1
0
0
0
0
0
0
0
0
0
0
1

CNS: coagulase-negative Staphylococcus, MRSA: Methicillin-resistant Staphylococcus
aureus, MSSA: Methicillin-sensitive Staphylococcus aureus, MRSE: Methicillinresistant Staphylococcus epidermidis, MRCNS: Methicillin-resistant coagulasenegative Staphylococcus, MSSE: Methicillin-sensitive Staphylococcus epidermidis.

Table 1
Patient demographics.
Type of surgery

Two-stage
Success group n ¼ 61

Two-stage
Failure group n ¼ 8

Multiple-stage
Success group n ¼ 6

Mean age at surgery (y) (range)
Male:Female
Diabetes mellitus (number)
Steroid therapy
Mean time from primary procedure to ﬁrst-stage revision (y) (range)
Mean time from ﬁrst-stage to second-stage revision (wk) (range)
Mean time from revised THA to ﬁnal follow-up (y) (range)

68 (32e86)
15:46
10
4
4 (0.1e14)
7 (5e13)4 (0.3e16)67 (50e81)
3:5
2
15 (0.3e16)8 (6e9)6 (0.7e13)

71 (59e84)
1:5
2
0
4 (0.5e12)
5 (4e7)6 (1e10)

THA: total hip arthroplasty.
3

K. Oe, H. Iida, R. Inokuchi et al.

Journal of Orthopaedic Science xxx (xxxx) xxx

worldwide, although for certain selected patients the one-stage
revision procedure can be feasible [3,4,9,31]. However, the twostage revision process makes it difﬁcult to assess the optimal
timing of reimplantation. This difﬁculty stems from two reasons:ﬁrst, prolonged antibiotic therapy can confound results, and second, the presence of unremoved ALAC may act as a scaffold towhich bioﬁlms attach and serve as foci of reinfection [32]. Thus, inthe second stage of two-stage revision THA, surgeons struggle withtwo decisions: when to plan for reimplantation, and whether toactually proceed to reimplantation at that point or to continue withfurther debridement (i.e. multiple-stage revision). In the current
study, we veriﬁed the timing of reimplantation in two-stage revision THA using serum CRP.
PJI diagnosis progressed after the introduction and modiﬁcationof MSIS criteria, but efforts continue to identify a reliable biomarker
that can be measured accurately and less invasively. CRP, anarchetype acute phase protein ﬁrst identiﬁed in 1930, is a very
commonly available serum biomarker [33]. It continues to be used
in ﬁrst-line screening tests for PJI and plays an important role ineffective monitoring during therapy. However, CRP often fails tonormalize after the infection is eradicated [20e22]. In two-stage
revision THA, some authors have reported difﬁculty in determining from CRP alone whether to perform THA or to perform
further debridement [10e15]. Dwyer et al. [14], reviewed 205 twostage revisions (132 TKAs and 73 THAs), compared hips with andwithout recurrent infection, and found no difference in mean preoperative serum CRP level between these two groups (p ¼ 0.40).
Stambough et al. [15] reviewed 291 two-stage revision procedures(146 TKAs and 145 THAs), and found that serum CRP levels were apoor marker of recurrent infection when compared between preresection and 6 weeks after resection (AUC ¼ 0.539). Nevertheless,these past reports did not compare CRP levels over time, and attempts to perform detailed CRP analysis across systemic reviews
and meta-analyses proved problematic.
For the current study, we retrospectively evaluated CRP levels
every week, and we used log2 (CRP) which yields more reliable
odds ratio estimates. Consequently, we were unable to predictfailure in the ﬁrst-staged surgery based on preoperative CRP levels,
and we were also unable to make predictions about the secondstaged surgery based on CRP levels during the ﬁrst 5 weeks.
However, we found a signiﬁcant difference in the log2 (CRP) at 3
weeks divided by that at 2 weeks, and we also found that a CRP
ratio of 4.0 or higher between week 3 and week 2 was associatedwith failure following two-stage revision THA. Similarly, Simon
et al. [34] reviewed 61 two-stage revision THAs for PJI without an
ALAC spacer and reported elevation of CRP levels in the failuregroup from week 2 to week 3 after resection. The AUC after ROC was
0.813 between the matched failure group and success group on day
24 (±1) postoperatively (p ¼ 0.001). Based on these ﬁndings, in
two-stage revision THA for PJI, patients who show elevated CRP
from 2 to 3 weeks after the ﬁrst stage should be considered forfurther debridement prior to reimplantation.

Fig. 3. The progression of mean C-reactive protein levels treated in two-stage andmultiple-stage revision total hip arthroplasty. Data are expressed as the means andstandard deviations.

Fig. 3 shows progression in mean CRP level. In two-stage revision THA, mean CRP levels at the second stage of surgery (reimplantation) in successful and failed cases were 8.8 ± 12.3 and10.3 ± 22.8, respectively (p ¼ 0.78). In multiple-stage revision THA,
mean CRP levels at the second and third stages of surgery were
27.8 ± 19.2 and 5.3 ± 3.7, respectively (p < 0.001). In the event of
failure after two-stage revision THA and multiple-stage revision
THA, mean CRP levels at 3 weeks were increased.
Table 3 shows ﬁndings for mean log2 (CRP) using logistic
regression. To predict failure preoperatively, sensitivity and speciﬁcity were plotted on an ROC curve (AUC 0.567; 95% CI
0.334e0.800). At 5 weeks, when the second-staged surgery wasscheduled, log2 (CRP) showed an AUC of 0.634 (95% CI 0.406e0.861).
Preoperatively, at 1, 2, 3, and 5 weeks, log2 (CRP) was not associatedwith failure of the procedure. A number of parameters were also
calculated using log2 (CRP) at 3 weeks after the ﬁrst-staged surgery(Table 3) because mean CRP levels at 3 weeks were increased in theevent of failure following two-stage or multiple-stage revision THA.
The log2 (CRP) at 3 weeks divided by that at 2 weeks showed asigniﬁcant difference (AUC 0.444; 95% CI 0.154e0.734), and a ratio of>4.0 between the 3-week and 2-week CRP levels values was associated with failures following two-stage revision THA.
4. Discussion
PJI continues to be one of the most severe complications in THA
and is the second most common cause of revision in the UnitedStated and the third in the United Kingdom [1,2]. Two-stage revision THA is considered the gold standard treatment for PJI
Table 3
Mean log2 (CRP) using logistic regression.
Mean log2 (CRP)

Logistic regression coefﬁcient

Odds ratio (95% CI)

p value

Preoperatively
At 1 week
At 2 weeks
At 3 weeks
At 5 weeks(3 weekse1 week)(3 weekse2 weeks)(3 weeks/1 week)(3 weeks/2 weeks)

0.094
0.243
0.075
0.039
0.071incalculable
0.469
0.154
0.498

0.937 (0.767e1.145)
0.845 (0.501e1.426)
0.949 (0.706e1.276)
0.973 (0.692e1.368)
0.952 (0.756e1.199)
incalculable
1.384 (0.928e2.064)
1.113 (1.022e1.212)
1.412 (1.124e1.774)

0.52330.52850.72980.87600.6758
incalculable
0.11090.01360.0031

CRP: C-reactive protein, CI: conﬁdence intervals.
4

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Acknowledgement

There are some limitations to this study. First, the small numberof cases, short follow-up period, and relatively few failed cases
made statistical analysis challenging and yielded a relatively ﬂat
AUC. Infection risks, including diabetes mellitus or steroid therapy,
also could not be statistically evaluated because of the small
number of failed cases. Second, treatment of PJIs involves the use ofa wide variety of antibiotics, so the conditions of treatment can varyconsiderably. In the second stage of surgery, the decision to reimplant the prosthetic or to switch to multiple-stage revision wasmade by the surgeon, with no ﬁrm criteria provided. Furthermore,in two-stage revision THA using cement spacers, the normalized
time interval of CRP level in the culture-negative PJI group was
shorter than in the culture-positive PJI group [35]. We did notcollect speciﬁc data regarding culture-negative PJI vs. culturepositive PJI, which may have also affected our results. Third, fordiagnosing PJI, several other markers including plasma ﬁbrinogen,synovial tests, interleukin-6, procalcitonin, tumor necrosis factor-a,
ﬂow cytometry, and next-generation sequencing, have proven to besuperior diagnostic tools, although serum CRP evaluation is moreaccurate than other serum traditional parameters such as whiteblood cell count, percentage of neutrophils, or neutrophils to
lymphocytes ratio [10,13,17,19]. Multiple variables may now be
included in decisions for reimplantation, since the modiﬁed MSIS
criteria included several new biomarkers [18].
In conclusion, 10-year survival rates were 85% (95% CI, 76e95)
and 100% for two-stage and multiple-stage revision THA, respectively. All of those who failed two-stage revision THA and all of
those who succeeded at multiple-stage revision THA showedelevated CRP levels 3 weeks after the ﬁrst surgery. In patients
whose multiple-stage revision was successful, CRP levels at thethird staged surgery were signiﬁcantly lower than at the timescheduled for the second-staged surgery. These ﬁndings emphasize
the importance of waiting until CRP has dropped to an appropriate
level before performing reimplantation. When the ratio of CRP
levels between 3 weeks and 2 weeks exceeds 4.0, further
debridement without reimplantation should be considered in thesecond stage of surgery.

The authors extend grateful thanks to Tomomi Oe for thesupervisor.
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IRB approval
This study was approved by our institutional review board.
Funding
This research did not receive any speciﬁc grant from funding
agencies in the public, commercial, or not-for-proﬁt sectors.
Authors' contributions
Each author made substantial contributions to the following
components of the project: conception, design, interpretation ofdata, drafting of the manuscript. All authors read and approved theﬁnal manuscript.
Study design
Clinical research (Retrospective cohort study). The study wasapproved by our institutional review board (H120167).
Declaration of competing interest
All authors have no conﬂicts of interest relevant to this article todeclare.
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