J Knee Surg 2023; 36(04): 354-361
DOI: 10.1055/s-0041-1733902
Original Article

Elevated ESR and CRP Prior to Second-Stage Reimplantation Knee Revision Surgery for Periprosthetic Joint Infection Are Associated with Increased Reinfection Rates

Christian Klemt
1   Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
,
Anand Padmanabha
1   Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
,
John G. Esposito
1   Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
,
Samuel Laurencin
1   Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
,
Evan J. Smith
1   Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
,
Young-Min Kwon
1   Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
› Author Affiliations
Funding None.
 

Abstract

Although two-stage revision surgery is considered as the most effective treatment for managing chronic periprosthetic joint infection (PJI), there is no current consensus on the predictors of optimal timing to second-stage reimplantation. This study aimed to compare clinical outcomes between patients with elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) prior to second-stage reimplantation and those with normalized ESR and CRP prior to second-stage reimplantation. We retrospectively reviewed 198 patients treated with two-stage revision total knee arthroplasty for chronic PJI. Cohorts included patients with: (1) normal level of serum ESR and CRP (n = 96) and (2) elevated level of serum ESR and CRP prior to second-stage reimplantation (n = 102). Outcomes including reinfection rates and readmission rates were compared between both cohorts. At a mean follow-up of 4.4 years (2.8–6.5 years), the elevated ESR and CRP cohort demonstrated significantly higher reinfection rates compared with patients with normalized ESR and CRP prior to second-stage reimplantation (33.3% vs. 14.5%, p < 0.01). Patients with both elevated ESR and CRP demonstrated significantly higher reinfection rates, when compared with patients with elevated ESR and normalized CRP (33.3% vs. 27.6%, p = 0.02) as well as normalized ESR and elevated CRP (33.3% vs. 26.3%, p < 0.01). This study demonstrates that elevated serum ESR and/or CRP levels prior to reimplantation in two-stage knee revision surgery for chronic PJI are associated with increased reinfection rate after surgery. Elevation of both ESR and CRP were associated with a higher risk of reinfection compared with elevation of either ESR or CRP, suggesting the potential benefits of normalizing ESR and CRP prior to reimplantation in treatment of chronic PJI.


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Two-stage revision arthroplasty, involving removal of the implants and placement of an antibiotic-loaded spacer followed by delayed reimplantation of a new prosthesis, is the current gold-standard treatment for chronic total knee arthroplasty (TKA) periprosthetic joint infections (PJIs). Many prior studies report a successful eradication of PJI in more than 80% of patients with this management strategy.[1] [2] In comparison, single-stage revision in patients with immunocompetence, identified organisms, and adequate soft tissue and bone stock is becoming an appealing alternative to the standard two-stage revision,[3] with a successful eradication of PJI being reported in 67 to 85% of patients.[4] [5] [6] The superior PJI eradication rates of two-stage revision surgery are associated with the use of an antibiotic-loaded spacer prior to TKA reimplantation that allows for an opportunity to assess the response to antibiotics for PJI clearance prior to TKA reimplantation.[7] [8] Although the optimal timing for second-stage reimplantation is guided by a combination of serum inflammatory markers, synovial fluid analysis, and clinical assessment of the treatment response,[9] [10] there is no gold standard method to determine PJI eradication at the time of reimplantation. The diagnostic accuracy of synovial aspiration results have been reported in studies (sensitivity 87%, specificity 90%),[11] [12] with other studies reporting an inferior diagnostic utility of aspiration results (sensitivity 50%, specificity 83%).[13] Additionally, the use of aspirate markers may be hindered by the lack of accessible synovial fluid or a “dry aspiration,” which is not uncommon in patients with an antibiotic cement spacer.[14] [15] For this reason, synovial fluid analysis is not routinely performed before reimplantation at many centers.[16]

Gram stain and frozen sections have the potential to provide intraoperative information to guide a decision whether to implant a new prosthesis or spacer exchange; however, Gram stain has not been recommended due to studies demonstrating its very low sensitivity (< 60%) to successfully guide reimplantation and predict reinfection following reimplantation.[17] [18] The utility of frozen section analysis is hindered by the current lack of a standardized thresholds for diagnosing infection. Due to these aforementioned limitations, serum erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are the most widely used parameters to guide the timing of reimplantation due to their low cost and ease of attainment.[24] However, the value of ESR and CRP in predicting persistent infection at reimplantation remains controversial.[11] In fact, normalization of these serum markers did not qualify as a final definition of PJI eradication in the Delphi criteria, which is the most widely utilized consensus metric for determining success after treatment of PJI.[19] Therefore, a progressive decline in ESR and CRP values without normalized levels along with the absence of clinical signs of PJI has been suggested as an acceptable prerequisite for proceeding with reimplantation.[20] [21] [22] There remains a paucity of studies evaluating the outcomes after second-stage reimplantation for PJI in cases in which serum ESR and CRP remain elevated prior to second-stage reimplantation. Therefore, this study aimed to evaluate clinical outcomes between patients with elevated ESR and CRP prior to second-stage reimplantation and those with both normalized ESR and CRP prior to second-stage reimplantation in patients with chronic knee PJI. The authors hypothesize that patients with elevated ESR and CRP prior to second-stage reimplantation will have inferior outcomes compared with patients with both normalized ESR and CRP prior to second-stage reimplantation.

Methods

Patients

A total of 198 patients who underwent two-stage knee revision surgery for chronic PJI (all McPherson et al infection type 3[23]) without systemic autoimmune diseases at a tertiary academic institution was evaluated in this Institutional Review Board-approved study. Serum ESR and CRP were recorded within 4 weeks prior to second-stage reimplantation, and at least 2 weeks after the end of the antibiotic treatment. The patients were divided into two groups: (1) 96 patients with normalized ESR and CRP prior to second-stage reimplantation, and (2) 102 patients with elevated ESR and CRP (with progressive decline) prior to second-stage reimplantation. The cohort of 102 patients with elevated ESR and CRP prior to second-stage reimplantation included 21 patients with both elevated ESR and elevated CRP prior to second-stage reimplantation, 47 patients with elevated ESR and normalized CRP prior to second-stage reimplantation, as well as 34 patients with normalized ESR and elevated CRP prior to second-stage reimplantation. An ESR greater than 30 mm/h and CRP greater than 10 mg/dL were defined as elevated values as defined by established standards in the literature.[24]

Patient charts were manually reviewed to obtain patient demographics, medical comorbidities, and preoperative laboratory findings. Clinical outcomes including reinfection rates, rerevision rates for aseptic reasons, 1-year amputation rates, 90-day death rates, and 30-, 60-, and 90-day readmission rates were also obtained. In concordance with previous literature,[25] [26] reinfection was defined according to the Musculoskeletal Infection Society criteria and obtained through a retrospective review of patient charts. Patients who did not undergo reimplantation for any reason, including those who required resection arthroplasty, retained static or articulating spacers, and/or underwent arthrodesis, were excluded from analysis. Additionally, patients with underlying medical conditions such as human immunodeficiency virus, liver disease, renal failure, steroid dependence, and chronic autoimmune diseases were excluded from analysis due to the potential impact of these medical conditions on serum markers and reinfection rates.[27] Patients with a follow-up of less than 2 years, incomplete data, or previous revision surgery were excluded from analysis.


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Surgical Technique

All surgical interventions were performed by fellowship-trained arthroplasty surgeons at a single tertiary referral institution. All revision TKA surgeries were performed using a medial parapatellar approach, regardless of the initial approach. All patients were treated with current two-stage revision techniques for chronic PJI,[5] which included the removal of all implant components, thorough debridement of foreign materials and debris, synovectomy, and insertion of antibiotic-loaded spacer during the first stage, followed by reimplantation of revision components during the second-stage surgery. In consultation with infectious diseases, the protocol included that an antibiotic-loaded spacer was implanted and patients received parenteral organism-specific antibiotic therapy for 6 to 8 weeks. The most commonly used antibiotic combination in the antibiotic-loaded spacer was 2 g of vancomycin and 2.4 g of tobramycin per 40 g package of cement. As per institutional protocol, an antibiotic holiday for 4 to 6 weeks was performed in all patients prior to second-stage re-implantation.


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Power Analysis

A statistical power analysis was performed for sample size estimation to evaluate clinical outcomes between patients with elevated ESR and CRP prior to second-stage reimplantation and those with both normalized ESR and CRP prior to second-stage reimplantation. Due to the paucity of studies that directly compare clinical outcomes between patients with elevated ESR and CRP prior to second-stage reimplantation and those with both normalized ESR and CRP prior to second-stage reimplantation, the power analysis was performed based on data from similarly designed previous study.[26] [28] [29] With an α = 0.05, power = 0.80, and the same sampling ratio, the projected sample size needed for this study is approximately 20 patients with elevated ESR and CRP prior to second-stage reimplantation and 40 patients with both normalized ESR and CRP prior to second-stage reimplantation.


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Statistical Analysis

The three cohorts with elevated serum marker as well as the normalized marker cohort were compared with regards to patient demographics, medical comorbidities, and clinical outcomes using descriptive statistics.[30] Continuous variables were compared using a Student's t-test, while categorical variables were compared using a Chi-squared test. All statistical analysis was performed in SPSS (SPSS Version 18.0, IBM Corp., Armonk, NY).[31]


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Results

This study included a total of 198 patients that underwent two-stage hip or knee revision surgery for chronic PJI: (1) 96 patients with normalized ESR and CRP prior to second-stage reimplantation, and (2) 102 patients with elevated ESR and CRP prior to second-stage reimplantation. The normalized marker cohort accounted for 48% of patients, while 10% of patients demonstrated an elevated ESR and elevated CRP (“elevated maker cohort”) prior to second-stage reimplantation. The patient cohort with elevated ESR and normalized CRP accounted for 24% of patients, while patients with normalized ESR and elevated CRP represented 18% of the patient cohort. The average ESR and CRP in the normalized marker cohort were 18.5 ± 13.5 mm/h and 6.4 ± 4.2 mg/dL, respectively ([Table 1]). The average serum markers for patients with both elevated ESR and elevated CRP were 75.2 ± 29.0 mm/h and 42.6 ± 26.8mg/dL, respectively ([Table 1]). The mean age of the cohorts was 65.2 ± 8.4 years, with an average body mass index of 32.1 ± 7.5 kg/m2. The average follow-up of the cohort was 4.4 years (2.8–6.5 years). There was no significant difference between the normalized marker cohort and the three cohorts with elevated serum makers with regards to patient demographics, medical comorbidities, and causative pathogens ([Tables 1] and [2]). Reinfections that occurred in the study cohort were mainly with the same organism as that from revision surgery. For 3 patients in the normalized ESR and normalized CRP cohort, 1 patient in the elevated ESR and elevated CRP cohort, 2 patients in the elevated ESR and normalized CRP cohort, and 2 patients in the normalized ESR and elevated CRP cohort, the organism differed between revision surgery and rerevision surgery.

Table 1

Comparison of patient demographics and preoperative infection markers between patients with normalized ESR and CRP as well as patients with elevated ESR and CRP

Normalized ESR and normalized CRP (n = 96)

Elevated ESR and elevated CRP (n = 21)

Elevated ESR and normalized CRP (n = 47)

Normalized ESR and elevated CRP (n = 34)

p-Value

Age (y)

65.6 ± 8.4

65.2 ± 8.7

64.6 ± 8.5

65.3 ± 8.3

0.64

Gender (M/F)

51/45

11/10

25/22

19/15

0.27

BMI (kg/m2)

31.9 ± 7.5

32.2 ± 7.4

31.7 ± 7.7

32.3 ± 7.4

0.51

Laterality (left/right)

53/43

13/8

27/20

18/16

0.33

Follow-up (y)

4.6 ± 1.6

4.2 ± 1.3

4.3 ± 1.4

4.4 ± 1.2

0.47

 ASA score

  1

15

5

6

7

0.54

  2

67

12

26

20

  3

13

4

14

7

  4

1

0

1

0

Comorbidities

 Smoking

9 (9.6%)

2 (9.5%)

4 (8.5%)

2 (5.8%)

0.56

 Drinking

22 (22.9%)

5 (23.8%)

9 (19.2%)

7 (20.5%)

0.77

 Drug abuse

5 (5.2%)

0 (0.0%)

0 (0.0%)

1 (2.9%)

0.53

 Depression

17 (17.7%)

3 (14.2%)

7 (14.8%)

6 (17.6%)

0.40

 Diabetes mellitus

20 (20.8%)

4 (19.0%)

9 (19.1%)

7 (20.5%)

0.72

 Malignancy

14 (14.6%)

2 (9.5%)

5 (10.6%)

5 (14.7%)

0.30

 Hypertension

54 (56.3%)

10 (47.6%)

23 (48.9%)

17 (50.0%)

0.49

Preop infection markers

 ESR (mm/h)

18.5 ± 13.5

75.2 ± 29.0

65.7 ± 26.1

21.2 ± 14.7

< 0.01

 CRP (mg/dL)

6.4 ± 4.2

42.6 ± 26.8

7.5 ± 4.9

35.1 ± 16.8

< 0.01

 ESR/CRP

3.2 ± 2.1

1.8 ± 1.4

9.4 ± 4.7

0.8 ± 1.9

< 0.01

 Synovial WBC (cells/µL)

1422.6 ± 627.4

1611.2 ± 956.8

2846.9 ± 1163.0

1313.5 ± 833.5

0.39

 Synovial PMN (%)

69.7 ± 22.2

74.2 ± 23.9

71.1 ± 22.0

72.3 ± 24.1

0.68

 Days to reimplantation

103.7 ± 56.2

112.1 ± 70.7

100.8 ± 61.6

107.4 ± 64.5

0.41

 Dynamic spacer (%)

81 (84.3%)

18 (85.7%)

39 (82.9%)

29 (85.2%)

0.52

Abbreviations: ASA, American Society of Anaesthesiologists; BMI, body mass index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PMN, polymorphonuclear; WBC, white blood cell.


Note: Bold values indicate statistical significance.


Table 2

Comparison of causative pathogens between patients with normalized ESR and CRP as well as patients with elevated ESR and CRP

Causative pathogen

Normalized ESR and normalized CRP (n = 96)

Elevated ESR and elevated CRP (n = 21)

Elevated ESR and normalized CRP (n = 47)

Normalized ESR and elevated CRP (n = 34)

p-Value

Unfavorable

0.51

 Methicillin-resistant Staphylococcus aureus (MRSA)

8

2

4

2

 Pseudomonas aeruginosa

3

0

1

1

 Anaerobes

7

2

3

3

 Negative culture

6

1

2

2

 Other gram negative organisms

13

3

7

4

 Mixed growth

11

2

6

4

Favorable

0.39

 Streptococcus species

17

4

9

7

 Staphylococcus species

13

3

7

4

 Coagulase-negative staphylococci

4

1

2

1

 Other Gram-positive organisms

2

0

1

0

 Propionibacterium acnes

3

1

1

1

 Staphylococcus aureus

7

2

3

3

 Other

2

0

1

2

Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.


With regards to postoperative complication rates, patients with both elevated ESR and elevated CRP prior to second-stage reimplantation demonstrated a significantly higher reinfection rate (33.3% vs. 14.5%, p < 0.01; [Table 3]), when compared with patients with normalized ESR and CRP prior to second-stage reimplantation. There was no significant difference between both cohorts for aseptic rerevisions (9.4% vs. 9.5%, p = 0.97), 1-year amputation rates (2.0% vs. 0.6%, p = 0.21), 90-day mortality rate (1.1% vs. 0.0%, p = 0.55), 30-day readmission (15.6% vs. 14.2%, p = 0.53), 60-day readmissions (16.7% vs. 19.0%, p = 0.62), and 90-day readmissions (18.7% vs. 19.0%, p = 0.73; [Table 3]).

Table 3

Comparison of postoperative complication rates between all study cohorts

Normalized ESR and normalized CRP ( n  = 96)

Elevated ESR and elevated CRP ( n  = 21)

Odds ratio (95% CI)

p -Value

Complication rates

 Reinfection rate (%)

14 (14.5%)

7 (33.3%)

1.37 (0.82–1.70)

< 0.01

 90-day mortality rate (%)

1 (1.1%)

0 (0.0%)

1.11 (0.93–1.21)

0.55

 1-year amputation rate (%)

2 (2.0%)

1 (0.6%)

1.09 (0.84–1.33)

0.21

 Rerevision rate (%)

9 (9.4%)

2 (9.5%)

1.05 (0.93–1.25)

0.97

 30-day readmission rate (%)

15 (15.6%)

3 (14.2%)

1.14 (0.93–1.37)

0.53

 60-day readmission rate (%)

16 (16.7%)

4 (19.0%)

1.10 (0.87–1.34)

0.62

 90-day readmission rate (%)

18 (18.7%)

4 (19.0%)

1.16 (0.94–1.44)

0.73

Normalized ESR and normalized CRP ( n  = 96)

Elevated ESR and normalized CRP ( n  = 47)

Odds ratio (95% CI)

p -Value

Complication rates

 Reinfection rate (%)

14 (14.5%)

13 (27.6%)

1.28 (0.88–1.50)

< 0.01

 90-day mortality rate (%)

1 (1.1%)

1 (2.1%)

1.04 (0.87–1.18)

0.44

 1-year amputation rate (%)

2 (2.0%)

1 (2.1%)

1.07 (0.93–1.24)

0.43

 Rerevision rate (%)

9 (9.4%)

5 (10.6%)

1.11 (0.88–1.35)

0.58

 30-day readmission rate (%)

15 (15.6%)

9 (19.1%)

1.16 (0.87–1.42)

0.30

 60-day readmission rate (%)

16 (16.7%)

8 (17.0%)

1.13 (0.84–1.36)

0.81

 90-day readmission rate (%)

18 (18.7%)

8 (17.0%)

1.10 (0.93–1.27)

0.65

Normalized ESR and normalized CRP ( n  = 96)

Normalized ESR and elevated CRP ( n  = 34)

Odds ratio (95% CI)

p -Value

Complication rates

 Reinfection rate (%)

14 (14.5%)

9 (26.3%)

1.25 (0.91–1.48)

< 0.01

 90-day mortality rate (%)

1 (1.1%)

1 (2.9%)

1.05 (0.93–1.15)

0.47

 1-year amputation rate (%)

2 (2.0%)

1 (3.0%)

1.07 (0.96–1.27)

0.73

 Rerevision rate (%)

9 (9.4%)

4 (11.7%)

1.11 (0.91–1.20)

0.41

 30-day readmission rate (%)

15 (15.6%)

6 (17.6%)

1.08 (0.95–1.26)

0.49

 60-day readmission rate (%)

16 (16.7%)

6 (17.6%)

1.09 (0.91–1.27)

0.43

 90-day readmission rate (%)

18 (18.7%)

7 (20.5%)

1.07 (0.95–1.22)

0.47

Abbreviations: CI, confidence interval; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.


Note: Bold values indicate statistical significance.


With regards to postoperative complications for patients with elevated ESR and normalized CRP prior to second-stage reimplantation, these patients demonstrated a significantly higher reinfection rate (27.6% vs. 14.5%, p < 0.01; [Table 3]), when compared with patients with normalized ESR and CRP prior to second-stage reimplantation. There was no significant difference between these cohorts for aseptic rerevisions (9.4% vs. 10.6%, p = 0.58), 1-year amputation rates (2.0% vs. 2.1%, p = 0.43), 90-day mortality rate (1.1% vs. 2.1%, p = 0.44), 30-day readmission (15.6% vs. 19.1%, p = 0.30), 60-day readmissions (16.7% vs. 17.0%, p = 0.81), and 90-day readmissions (18.7% vs. 17.0%, p = 0.65; [Table 3]).

With regards to postoperative complications for patients with normalized ESR and elevated CRP prior to second-stage reimplantation, these patients demonstrated a significantly higher reinfection rate (26.3% vs. 14.5%, p < 0.01; [Table 4]), when compared with patients with normalized ESR and CRP prior to second-stage reimplantation. There was no significant difference between these cohorts for aseptic rerevisions (11.7% vs. 9.4%, p = 0.41), 1-year amputation rates (2.0% vs. 3.0%, p = 0.73), 90-day mortality rate (1.1% vs. 2.9%, p = 0.47), 30-day readmission (15.6% vs. 17.6%, p = 0.49), 60-day readmissions (16.7% vs. 17.6%, p = 0.43), and 90-day readmissions (18.7% vs. 20.5%, p = 0.47; [Table 4]).

Table 4

Comparison of postoperative complication rates between study cohorts with elevated serum markers

Elevated ESR and elevated CRP ( n  = 21)

Elevated ESR and normalized CRP ( n  = 47)

Odds ratio (95% CI)

p -Value

Complication rates

 Reinfection rate (%)

7 (33.3%)

13 (27.6%)

1.18 (0.91–1.33)

0.02

 90-day mortality rate (%)

0 (0.0%)

1 (2.1%)

1.05 (0.94–1.10)

0.45

 1-year amputation rate (%)

1 (0.6%)

1 (2.1%)

1.09 (0.92–1.18)

0.21

 Rerevision rate (%)

2 (9.5%)

5 (10.6%)

1.02 (0.91–1.07)

0.84

30-day readmission rate (%)

3 (14.2%)

9 (19.1%)

1.08 (0.96–1.11)

0.26

60-day readmission rate (%)

4 (19.0%)

8 (17.0%)

1.07 (0.94–1.16)

0.76

90-day readmission rate (%)

4 (19.0%)

8 (17.0%)

1.05 (0.96–1.07)

0.63

Elevated ESR and elevated CRP ( n  = 21)

Normalized ESR and elevated CRP ( n  = 34)

Odds ratio (95% CI)

p -Value

Complication rates

 Reinfection rate (%)

7 (33.3%)

9 (26.3%)

1.25 (0.92–1.38)

< 0.01

 90-day mortality rate (%)

0 (0.0%)

1 (2.9%)

1.06 (0.92–1.19)

0.33

 1-year amputation rate (%)

1 (0.6%)

1 (3.0%)

1.12 (0.93–1.29)

0.15

 Rerevision rate (%)

2 (9.5%)

4 (11.7%)

1.04 (0.95–1.17)

0.43

30-day readmission rate (%)

3 (14.2%)

5 (14.7%)

1.01 (0.97–1.04)

0.96

60-day readmission rate (%)

4 (19.0%)

6 (17.6%)

1.07 (0.94–1.18)

0.75

90-day readmission rate (%)

4 (19.0%)

7 (20.5%)

1.05 (0.95–1.15)

0.71

Elevated ESR and normalized CRP ( n  = 47)

Normalized ESR and elevated CRP ( n  = 34)

Odds ratio (95% CI )

p -Value

Complication rates

 Reinfection rate (%)

13 (27.6%)

9 (26.3%)

1.11 (0.95–1.23)

0.61

 90-day mortality rate (%)

1 (2.1%)

1 (2.9%)

1.07 (0.96–1.13)

0.85

 1-year amputation rate (%)

1 (2.1%)

1 (3.0%)

1.06 (0.92–1.17)

0.53

 Rerevision rate (%)

5 (10.6%)

4 (11.7%)

1.04 (0.89–1.19)

0.77

30-day readmission rate (%)

9 (19.1%)

6 (17.6%)

1.03 (0.97–1.15)

0.59

60-day readmission rate (%)

8 (17.0%)

6 (17.6%)

1.02 (0.96–1.09)

0.95

90-day readmission rate (%)

8 (17.0%)

7 (20.5%)

1.06 (0.94–1.13)

0.75

Abbreviations: CI, confidence interval; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.


Note: Bold values indicate statistical significance.


Subgroup analysis for patients with elevated serum markers demonstrated that patients with both elevated ESR and elevated CRP demonstrated significantly higher reinfection rates, when compared with patients with elevated ESR and normalized CRP (33.3% vs. 27.6%, p = 0.02; [Table 4]), as well as patients with normalized ESR and elevated CRP (33.3% vs. 26.3%, p < 0.01). There was no significant difference in reinfection rates between patients with elevated ESR and normalized CRP and patients with normalized ESR and elevated CRP (27.6% vs. 26.3%, p = 0.61). There was no significant difference between the three cohorts with elevated serum markers with regards to rerevision rate, 90-day mortality rate, 1-year amputation rate, and readmission rates with 30, 60, and 90 days ([Table 4]).


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Discussion

Currently, serological markers such as ESR and CRP are the most widely utilized parameters to determine optimal timing of reimplantation in two-stage revision arthroplasty due to their high availability and low cost. However, the utility of ESR and CRP in predicting reinfection prior to second-stage revision arthroplasty has been questioned, with a recent meta-analysis reporting sensitivities and specificities for ESR and CRP of 79 and 82% as well as 83 and 85%, respectively.[11] Prior studies have demonstrated that a progressive decline in ESR and CRP is a satisfactory indication for reimplantation in the absence of clinical signs of PJI.[20] [22] [32] However, there is a paucity of studies evaluating the impact of persistently elevated serum markers on outcomes after revision surgery for chronic PJI. The findings of this study demonstrate that patients with elevated ESR and/or elevated CRP prior to second-stage TKA reimplantation demonstrate a significantly higher reinfection rate at 4.2 years' follow-up. Subgroup analysis has demonstrated that patients with both elevated ESR and CRP demonstrate significantly higher reinfection rates, when compared with patients with elevated ESR and normalized CRP as well as patients with normalized ESR and elevated CRP, suggesting that an elevation of both serum markers prior to second-stage TKA reimplantation is associated with an increased risk of reinfection.

Lindsay et al reported reinfections in 5 of 19 patients (26%) with both elevated ESR and CRP prior to second-stage TKA reimplantation at 2-year follow-up.[28] Similarly, Kusuma et al reported PJI recurrence in 8 of 76 patients (12%) with both elevated ESR and CRP prior to second-stage TKA reimplantation at 2-year follow-up.[25] In concordance with these studies, Ghanem et al reported reinfections in 23 of 109 patients (23%) with both elevated ESR and CRP prior to second-stage reimplantation at 2-year follow-up, suggesting potential benefits of normalizing ESR and CRP prior to TKA reimplantation in treatment of PJI.[29] In contrast to these studies, Shukla et al investigated 86 consecutive patients with chronic PJI treated with two-stage revision surgery, demonstrating that there was no PJI recurrence in all patients with both elevated ESR and CRP prior to second-stage reimplantation.[26] Our findings are in concordance with previous literature,[25] [28] [29] demonstrating that patients with both elevated ESR and CRP prior to second-stage TKA reimplantation demonstrated a higher reinfection risk at 4.1 years' follow-up, when compared with patients with normalized ESR and CRP prior to second-stage reimplantation. This suggests that normalizing both ESR and CRP prior to reimplantation has the potential to decrease reinfection rates following two-stage revision TKA in the management of chronic PJI.

The significance of normalizing both ESR and CRP prior to second-stage reimplantation may be based on multiple factors. First, CRP is a nonspecific acute phase reactant assisting in phagocytosis of pathogens, and hence CRP levels are often proportional to the intensity of an ongoing infectious process.[33] However, cytokines induced by noninfectious causes, such as tissue injury after trauma or surgery, may also cause elevations in CRP.[33] Hence, decreasing trends in serum markers may be more reflective of progressive soft tissue recovery from the index revision surgery rather than eradication of infection. Second, mild elevations in markers after an antibiotic holiday may similarly be indicative of insidious development of a resistant microorganism secondary to prolonged antibiotic therapy or persistent subclinical infection with a low virulence organism such as coagulase negative Staphylococcus. These patients with declining, but not normalized, serum markers may be at increased risk for reinfection after reimplantation, as ESR and CRP are known to be highly sensitive but not specific markers of inflammation, with negative predictive values approaching 100%.[32] This implies that their utility is primarily as a “rule out” test, and as such, they offer limited clinical contribution in the absence of normalized values.

The findings of this study additionally illustrate increased reinfection rates for patients with either elevated ESR or elevated CRP, when compared with patients with both normalized ESR and CRP. This suggests that even the elevation of a single serum marker prior to second-stage TKA reimplantation is associated with increased reinfection rates. Similar observations were made by Xu et al, reporting associations between an either elevated serum ESR or an elevated serum CRP prior to second-stage TKA reimplantation and an increased reinfection risk, based on which the authors suggested the normalization of both ESR and CRP prior to TKA reimplantation to mitigate this risk.[34] Equally, Li et al reported that an elevated ESR was associated with an increased risk for postoperative complications, in a study with 167 TKA patients investigating risk factors for poor postoperative patients outcomes.[35] [36]

We performed subgroup analysis for patients with elevated serum markers prior to second-stage TKA reimplantation to investigate which serum marker has the strongest effect on reinfection rates. The study findings demonstrate that patients with both elevated ESR and CRP demonstrate a significantly higher risk of reinfection, when compared with patients with elevated ESR and normalized CRP as well as patients with normalized ESR and elevated CRP. The present study did not observe any significant difference in reinfection rates between patients with either elevated ESR or elevated CRP. This suggests that an elevation of both serum markers prior to second-stage TKA reimplantation is associated with a much higher reinfection risk, when compared with only ESR or only CRP being elevated, with no significant difference between an elevated ESR or an elevated CRP. Although there is a paucity of studies to directly compare the effect of elevated serum markers prior to second-stage reimplantation on reinfection rates, Ghanem et al reported a 13 and 15% increased reinfection risk respectively for patients with both elevated ESR and elevated CRP, when compared with patients with elevated ESR and normalized CRP as well as patients with normalized ESR and elevated CRP, illustrating the increased risk of reinfection with both elevated ESR and elevated CRP prior to second-stage TKA reimplantation in treatment of PJI.[29]

The findings of this study need to be interpreted in light of several limitations. First, this study has limitations inherent to all retrospective cohort designs such as differential and nondifferential misclassification bias and selection bias. Second, there may have been differences in the postoperative protocol for patients in the course of this study duration. However, this represents a common limitation of retrospective studies. Lastly, although there was no statistically significant difference between all study cohorts for a multitude of patient and surgical factors, differences could still exist between all study groups for factors that were not considered for analysis such as local extremity grade, bone loss, or soft tissue conditions. However, similar limitations were reported by numerous prior studies on this topic.[6] [29]

In conclusion, this study demonstrated significantly increased reinfection rates for patients with elevated serum ESR and/or CRP prior to the reimplantation stage of two-stage revision in the management of chronic knee PJI. Elevation of both ESR and CRP were associated with a higher risk of reinfection compared with elevation of either ESR or CRP, suggesting the potential benefits of normalizing both ESR and CRP prior to TKA reimplantation in treatment of chronic PJI to reduce the risk of recurrent infections.


#
#

Conflict of Interest

None declared.

Note

All data will be made available through contacting the corresponding author. All code used in this includes basic Matlab functions. The study was approved by institutional review board. All patients consented prior to participation in this study.


Authors' Contributions

C.K.: study design, data collection, analysis, and write-up. A.P.: data collection, analysis, and write-up. J.G.E.: write-up. S.L.: write-up. E.J.S.: write-up. Y.-M.K.: study design and analysis.


  • References

  • 1 Wang Q, Goswami K, Kuo F-C, Xu C, Tan TL, Parvizi J. Two-stage exchange arthroplasty for periprosthetic joint infection: the rate and reason for the attrition after the first stage. J Arthroplasty 2019; 34 (11) 2749-2756
  • 2 Romanò CL, Gala L, Logoluso N, Romanò D, Drago L. Two-stage revision of septic knee prosthesis with articulating knee spacers yields better infection eradication rate than one-stage or two-stage revision with static spacers. Knee Surg Sports Traumatol Arthrosc 2012; 20 (12) 2445-2453
  • 3 Zahar A, Kendoff DO, Klatte TO, Gehrke TA. Can good infection control be obtained in one-stage exchange of the infected TKA to a rotating hinge design? 10-year results. Clin Orthop Relat Res 2016; 474 (01) 81-87
  • 4 Singer J, Merz A, Frommelt L, Fink B. High rate of infection control with one-stage revision of septic knee prostheses excluding MRSA and MRSE. Clin Orthop Relat Res 2012; 470 (05) 1461-1471
  • 5 Haddad FS, Sukeik M, Alazzawi S. Is single-stage revision according to a strict protocol effective in treatment of chronic knee arthroplasty infections?. Clin Orthop Relat Res 2015; 473 (01) 8-14
  • 6 Klemt C, Tirumala V, Oganesyan R, Xiong L, den Kieboom Jn, Kwon Y-M. Single-stage revision of the infected total knee arthroplasty is associated with improved functional outcomes: a propensity score matched cohort study. J Arthroplasty 2020; ; (July) DOI: 10.1016/j.arth.2020.07.012.
  • 7 Gomez MM, Tan TL, Manrique J, Deirmengian GK, Parvizi J. The fate of spacers in the treatment of periprosthetic joint infection. J Bone Joint Surg Am 2015; 97 (18) 1495-1502
  • 8 Klemt C, Smith EJ, Tirumala V, Bounajem G, van den Kieboom J, Kwon Y-M. Outcomes and risk factors associated with 2-stage reimplantation requiring an interim spacer exchange for periprosthetic joint infection. J Arthroplasty 2020; ; (November) DOI: 10.1016/j.arth.2020.09.012.
  • 9 Mont MA, Waldman BJ, Hungerford DS. Evaluation of preoperative cultures before second-stage reimplantation of a total knee prosthesis complicated by infection. A comparison-group study. J Bone Joint Surg Am 2000; 82 (11) 1552-1557
  • 10 Pignatti G, Nitta S, Rani N. et al. Two stage hip revision in periprosthetic infection: results of 41 cases. Open Orthop J 2010; 4: 193-200
  • 11 Carli AV, Abdelbary H, Ahmadzai N. et al. Diagnostic accuracy of serum, synovial, and tissue testing for chronic periprosthetic joint infection after hip and knee replacements: a systematic review. J Bone Joint Surg Am 2019; 101 (07) 635-649
  • 12 Gehrke T, Lausmann C, Citak M, Bonanzinga T, Frommelt L, Zahar A. The accuracy of the alpha defensin lateral flow device for diagnosis of periprosthetic joint infection: comparison with a gold standard. J Bone Joint Surg Am 2018; 100 (01) 42-48
  • 13 Ottink KD, Strahm C, Muller-Kobold A, Sendi P, Wouthuyzen-Bakker M. Factors to consider when assessing the diagnostic accuracy of synovial leukocyte count in periprosthetic joint infection. J Bone Jt Infect 2019; 4 (04) 167-173
  • 14 Newman JM, George J, Klika AK. et al. What is the diagnostic accuracy of aspirations performed on hips with antibiotic cement spacers?. Clin Orthop Relat Res 2017; 475 (01) 204-211
  • 15 Partridge DG, Winnard C, Townsend R, Cooper R, Stockley I. Joint aspiration, including culture of reaspirated saline after a ‘dry tap’, is sensitive and specific for the diagnosis of hip and knee prosthetic joint infection. Bone Joint J 2018; 100-B (06) 749-754
  • 16 Srivastava K, Bozic KJ, Silverton C, Nelson AJ, Makhni EC, Davis JJ. Reconsidering strategies for managing chronic periprosthetic joint infection in total knee arthroplasty: using decision analytics to find the optimal strategy between one-stage and two-stage total knee revision. J Bone Joint Surg Am 2019; 101 (01) 14-24
  • 17 Chimento GF, Finger S, Barrack RL. Gram stain detection of infection during revision arthroplasty. J Bone Joint Surg Br 1996; 78 (05) 838-839
  • 18 Bauer TW, Parvizi J, Kobayashi N, Krebs V. Diagnosis of periprosthetic infection. J Bone Joint Surg Am 2006; 88 (04) 869-882
  • 19 Diaz-Ledezma C, Higuera CA, Parvizi J. Success after treatment of periprosthetic joint infection: a Delphi-based international multidisciplinary consensus. Clin Orthop Relat Res 2013; 471 (07) 2374-2382
  • 20 Burnett RSJ, Kelly MA, Hanssen AD, Barrack RL. Technique and timing of two-stage exchange for infection in TKA. Clin Orthop Relat Res 2007; 464 (464) 164-178
  • 21 Huang H-T, Su J-Y, Chen S-K. The results of articulating spacer technique for infected total knee arthroplasty. J Arthroplasty 2006; 21 (08) 1163-1168
  • 22 Chen S-Y, Hu C-C, Chen C-C, Chang Y-H, Hsieh P-H. Two-stage revision arthroplasty for periprosthetic hip infection: mean follow-up of ten years. BioMed Res Int 2015; 2015: 345475
  • 23 McPherson EJ, Woodson C, Holtom P, Roidis N, Shufelt C, Patzakis M. Periprosthetic total hip infection: outcomes using a staging system. Clin Orthop Relat Res 2002; (403) 8-15
  • 24 Parvizi J, Zmistowski B, Berbari EF. et al. New definition for periprosthetic joint infection: from the Workgroup of the Musculoskeletal Infection Society. Clin Orthop Relat Res 2011; 469 (11) 2992-2994
  • 25 Kusuma SK, Ward J, Jacofsky M, Sporer SM, Della Valle CJ. What is the role of serological testing between stages of two-stage reconstruction of the infected prosthetic knee?. Clin Orthop Relat Res 2011; 469 (04) 1002-1008
  • 26 Shukla SK, Ward JP, Jacofsky MC, Sporer SM, Paprosky WG, Della Valle CJ. Perioperative testing for persistent sepsis following resection arthroplasty of the hip for periprosthetic infection. J Arthroplasty 2010; 25 (6, Suppl): 87-91
  • 27 Stambough JB, Curtin BM, Odum SM, Cross MB, Martin JR, Fehring TK. Does change in ESR and CRP guide the timing of two-stage arthroplasty reimplantation?. Clin Orthop Relat Res 2019; 477 (02) 364-371
  • 28 Lindsay CP, Olcott CW, Del Gaizo DJ. ESR and CRP are useful between stages of 2-stage revision for periprosthetic joint infection. Arthroplast Today 2017; 3 (03) 183-186
  • 29 Ghanem E, Azzam K, Seeley M, Joshi A, Parvizi J. Staged revision for knee arthroplasty infection: what is the role of serologic tests before reimplantation?. Clin Orthop Relat Res 2009; 467 (07) 1699-1705
  • 30 Mehrani A, Sorolla MG, Makarenko T, Jacobson AJ. A new 1–1-4 pattern of magnetic exchange interactions in a cubane core tetranuclear copper (II) complex. Polyhedron 2021; 199: 115088
  • 31 Aron ZD, Mehrani A, Hoffer ED. et al. trans-Translation inhibitors bind to a novel site on the ribosome and clear Neisseria gonorrhoeae in vivo. Nat Commun 2021; 12 (01) 1799
  • 32 Klemt C, Tirumala V, Smith EJ, Padmanabha A, Kwon Y-M. Development of a preoperative risk calculator for re-infection following revision surgery for periprosthetic joint infection. J Arthroplasty 2020; (August) DOI: 10.1016/j.arth.2020.08.004.
  • 33 Bray C, Bell LN, Liang H. et al. Erythrocyte sedimentation rate and C-reactive protein measurements and their relevance in clinical medicine. WMJ 2016; 115 (06) 317-321
  • 34 Xu C, Guo H, Qu P, Fu J, Kuo F-C, Chen J-Y. Preoperatively elevated serum inflammatory markers increase the risk of periprosthetic joint infection following total knee arthroplasty in patients with osteoarthritis. Ther Clin Risk Manag 2018; 14: 1719-1724
  • 35 Li G, Weng J, Xu C, Wang D, Xiong A, Zeng H. Factors associated with the length of stay in total knee arthroplasty patients with the enhanced recovery after surgery model. J Orthop Surg Res 2019; 14 (01) 343
  • 36 Mehrani A, Ahmadvand P, Mehdizadeh Barforushi M, Mehrani K. Double functionalized nanoporous magnetic gadolinium–silica composite for doxorubicin delivery. J Inorg Organomet Polym Mater 2016; 26 (01) 226-232

Address for correspondence

Young-Min Kwon, MD, PhD
Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School
55 Fruit Street, Yawkey Suite 3B, Boston, MA 02114

Publication History

Received: 04 January 2021

Accepted: 21 June 2021

Article published online:
10 August 2021

© 2021. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

  • References

  • 1 Wang Q, Goswami K, Kuo F-C, Xu C, Tan TL, Parvizi J. Two-stage exchange arthroplasty for periprosthetic joint infection: the rate and reason for the attrition after the first stage. J Arthroplasty 2019; 34 (11) 2749-2756
  • 2 Romanò CL, Gala L, Logoluso N, Romanò D, Drago L. Two-stage revision of septic knee prosthesis with articulating knee spacers yields better infection eradication rate than one-stage or two-stage revision with static spacers. Knee Surg Sports Traumatol Arthrosc 2012; 20 (12) 2445-2453
  • 3 Zahar A, Kendoff DO, Klatte TO, Gehrke TA. Can good infection control be obtained in one-stage exchange of the infected TKA to a rotating hinge design? 10-year results. Clin Orthop Relat Res 2016; 474 (01) 81-87
  • 4 Singer J, Merz A, Frommelt L, Fink B. High rate of infection control with one-stage revision of septic knee prostheses excluding MRSA and MRSE. Clin Orthop Relat Res 2012; 470 (05) 1461-1471
  • 5 Haddad FS, Sukeik M, Alazzawi S. Is single-stage revision according to a strict protocol effective in treatment of chronic knee arthroplasty infections?. Clin Orthop Relat Res 2015; 473 (01) 8-14
  • 6 Klemt C, Tirumala V, Oganesyan R, Xiong L, den Kieboom Jn, Kwon Y-M. Single-stage revision of the infected total knee arthroplasty is associated with improved functional outcomes: a propensity score matched cohort study. J Arthroplasty 2020; ; (July) DOI: 10.1016/j.arth.2020.07.012.
  • 7 Gomez MM, Tan TL, Manrique J, Deirmengian GK, Parvizi J. The fate of spacers in the treatment of periprosthetic joint infection. J Bone Joint Surg Am 2015; 97 (18) 1495-1502
  • 8 Klemt C, Smith EJ, Tirumala V, Bounajem G, van den Kieboom J, Kwon Y-M. Outcomes and risk factors associated with 2-stage reimplantation requiring an interim spacer exchange for periprosthetic joint infection. J Arthroplasty 2020; ; (November) DOI: 10.1016/j.arth.2020.09.012.
  • 9 Mont MA, Waldman BJ, Hungerford DS. Evaluation of preoperative cultures before second-stage reimplantation of a total knee prosthesis complicated by infection. A comparison-group study. J Bone Joint Surg Am 2000; 82 (11) 1552-1557
  • 10 Pignatti G, Nitta S, Rani N. et al. Two stage hip revision in periprosthetic infection: results of 41 cases. Open Orthop J 2010; 4: 193-200
  • 11 Carli AV, Abdelbary H, Ahmadzai N. et al. Diagnostic accuracy of serum, synovial, and tissue testing for chronic periprosthetic joint infection after hip and knee replacements: a systematic review. J Bone Joint Surg Am 2019; 101 (07) 635-649
  • 12 Gehrke T, Lausmann C, Citak M, Bonanzinga T, Frommelt L, Zahar A. The accuracy of the alpha defensin lateral flow device for diagnosis of periprosthetic joint infection: comparison with a gold standard. J Bone Joint Surg Am 2018; 100 (01) 42-48
  • 13 Ottink KD, Strahm C, Muller-Kobold A, Sendi P, Wouthuyzen-Bakker M. Factors to consider when assessing the diagnostic accuracy of synovial leukocyte count in periprosthetic joint infection. J Bone Jt Infect 2019; 4 (04) 167-173
  • 14 Newman JM, George J, Klika AK. et al. What is the diagnostic accuracy of aspirations performed on hips with antibiotic cement spacers?. Clin Orthop Relat Res 2017; 475 (01) 204-211
  • 15 Partridge DG, Winnard C, Townsend R, Cooper R, Stockley I. Joint aspiration, including culture of reaspirated saline after a ‘dry tap’, is sensitive and specific for the diagnosis of hip and knee prosthetic joint infection. Bone Joint J 2018; 100-B (06) 749-754
  • 16 Srivastava K, Bozic KJ, Silverton C, Nelson AJ, Makhni EC, Davis JJ. Reconsidering strategies for managing chronic periprosthetic joint infection in total knee arthroplasty: using decision analytics to find the optimal strategy between one-stage and two-stage total knee revision. J Bone Joint Surg Am 2019; 101 (01) 14-24
  • 17 Chimento GF, Finger S, Barrack RL. Gram stain detection of infection during revision arthroplasty. J Bone Joint Surg Br 1996; 78 (05) 838-839
  • 18 Bauer TW, Parvizi J, Kobayashi N, Krebs V. Diagnosis of periprosthetic infection. J Bone Joint Surg Am 2006; 88 (04) 869-882
  • 19 Diaz-Ledezma C, Higuera CA, Parvizi J. Success after treatment of periprosthetic joint infection: a Delphi-based international multidisciplinary consensus. Clin Orthop Relat Res 2013; 471 (07) 2374-2382
  • 20 Burnett RSJ, Kelly MA, Hanssen AD, Barrack RL. Technique and timing of two-stage exchange for infection in TKA. Clin Orthop Relat Res 2007; 464 (464) 164-178
  • 21 Huang H-T, Su J-Y, Chen S-K. The results of articulating spacer technique for infected total knee arthroplasty. J Arthroplasty 2006; 21 (08) 1163-1168
  • 22 Chen S-Y, Hu C-C, Chen C-C, Chang Y-H, Hsieh P-H. Two-stage revision arthroplasty for periprosthetic hip infection: mean follow-up of ten years. BioMed Res Int 2015; 2015: 345475
  • 23 McPherson EJ, Woodson C, Holtom P, Roidis N, Shufelt C, Patzakis M. Periprosthetic total hip infection: outcomes using a staging system. Clin Orthop Relat Res 2002; (403) 8-15
  • 24 Parvizi J, Zmistowski B, Berbari EF. et al. New definition for periprosthetic joint infection: from the Workgroup of the Musculoskeletal Infection Society. Clin Orthop Relat Res 2011; 469 (11) 2992-2994
  • 25 Kusuma SK, Ward J, Jacofsky M, Sporer SM, Della Valle CJ. What is the role of serological testing between stages of two-stage reconstruction of the infected prosthetic knee?. Clin Orthop Relat Res 2011; 469 (04) 1002-1008
  • 26 Shukla SK, Ward JP, Jacofsky MC, Sporer SM, Paprosky WG, Della Valle CJ. Perioperative testing for persistent sepsis following resection arthroplasty of the hip for periprosthetic infection. J Arthroplasty 2010; 25 (6, Suppl): 87-91
  • 27 Stambough JB, Curtin BM, Odum SM, Cross MB, Martin JR, Fehring TK. Does change in ESR and CRP guide the timing of two-stage arthroplasty reimplantation?. Clin Orthop Relat Res 2019; 477 (02) 364-371
  • 28 Lindsay CP, Olcott CW, Del Gaizo DJ. ESR and CRP are useful between stages of 2-stage revision for periprosthetic joint infection. Arthroplast Today 2017; 3 (03) 183-186
  • 29 Ghanem E, Azzam K, Seeley M, Joshi A, Parvizi J. Staged revision for knee arthroplasty infection: what is the role of serologic tests before reimplantation?. Clin Orthop Relat Res 2009; 467 (07) 1699-1705
  • 30 Mehrani A, Sorolla MG, Makarenko T, Jacobson AJ. A new 1–1-4 pattern of magnetic exchange interactions in a cubane core tetranuclear copper (II) complex. Polyhedron 2021; 199: 115088
  • 31 Aron ZD, Mehrani A, Hoffer ED. et al. trans-Translation inhibitors bind to a novel site on the ribosome and clear Neisseria gonorrhoeae in vivo. Nat Commun 2021; 12 (01) 1799
  • 32 Klemt C, Tirumala V, Smith EJ, Padmanabha A, Kwon Y-M. Development of a preoperative risk calculator for re-infection following revision surgery for periprosthetic joint infection. J Arthroplasty 2020; (August) DOI: 10.1016/j.arth.2020.08.004.
  • 33 Bray C, Bell LN, Liang H. et al. Erythrocyte sedimentation rate and C-reactive protein measurements and their relevance in clinical medicine. WMJ 2016; 115 (06) 317-321
  • 34 Xu C, Guo H, Qu P, Fu J, Kuo F-C, Chen J-Y. Preoperatively elevated serum inflammatory markers increase the risk of periprosthetic joint infection following total knee arthroplasty in patients with osteoarthritis. Ther Clin Risk Manag 2018; 14: 1719-1724
  • 35 Li G, Weng J, Xu C, Wang D, Xiong A, Zeng H. Factors associated with the length of stay in total knee arthroplasty patients with the enhanced recovery after surgery model. J Orthop Surg Res 2019; 14 (01) 343
  • 36 Mehrani A, Ahmadvand P, Mehdizadeh Barforushi M, Mehrani K. Double functionalized nanoporous magnetic gadolinium–silica composite for doxorubicin delivery. J Inorg Organomet Polym Mater 2016; 26 (01) 226-232