1 Background

Periprosthetic joint infection (PJI) after total knee arthroplasty (TKA) is a major complication¹ and remains a devastating and challenging complication after TKA.² Of decisive importance for the successful therapy of a PJI is an early and reliable diagnosis, which enables quick initiation of therapy and may make it possible to salvage the prosthesis.^3,4 The standard serum C reactive protein (CRP) is an acute phase protein produced in the liver and is elevated in case of inflammation or infection. The standard serum CRP assay is routine tests in the diagnostic workup for infection, while Bauer and Parvizi et al.^5,6 described that if a suspected diagnosis PJI is already available clinically, the CRP values show better specificity. White J et al. revealed that after TKA, the CRP value increases significantly and achieves its maximum value between the second and third postoperative day and then falls again to the normal level after 3–6 weeks in the case of a complication-free potential postoperative course.⁷ However, patients with no serum CRP negative conversion have been treated with antibiotics to avoid the morbidity of PJI. The Musculoskeletal Infection Society (MSIS) reported that there is a danger of administering antibiotics ineffectively for a long period of time, thus affecting the accuracy of PJI diagnosis.⁸ Therefore, we investigated whether there was any factor of delaying negative conversion of CRP after TKA except PJI.

Recently, Shahi A et al.⁸ reported that the serum D-Dimer test demonstrated better sensitivity, 89% and better specificity, 93%, for diagnosing PJI. D-Dimer of the coagulation marker is activated after TKA and has traditionally been used as a screening test for detecting venous thromboembolism (VTE). Perrier et al.⁹ reported that drilling, bone saw use, and bone excavation result in the long-term elevation of D-Dimer and fibrin degradation product (FDP) of fibrinolysis marker. When we examined retrospectively, we suspected that the coagulation marker would show high values as a result of delayed CRP negative conversion after TKA (without PJI and VTE): therefore, we hypothesized that patients with high level of D-Dimer and FDP values after TKA might delay the timing of CRP negative conversion. The purpose of the present study is to investigate the factors associated with prolongation of the negative conversion of CRP, with the exclusion of PJI patients.

2 Methods

We retrospectively researched the hospital database for a total of 121 patients who performed primary TKA for medial osteoarthritis of the knee from August 2014 to August 2016. Patients with the onset of PJI were not included. Out of 121 patients, 75 patients were excluded from this study due to anticoagulant oral administration before and after TKA, VTE with the use of lower limb venous echocardiography before and after TKA, re-elevation of CRP values, and morbidity of PJI (according to the diagnostic criteria of the Musculoskeletal Infection Society (MSIS)¹² (Fig. 1).

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Fig. 1 Flow diagram of illustrating patients' enrollment, allocation and analysis.

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The 46 patients were divided into two groups: Group A: ≥20 days (n = 23) and Group B: <20 days (n = 23), according to the number of days required for negative conversion of CRP values to occur (using 20.3 days: the mean duration of hospitalization after TKA in our hospital, as the reference value⁶). Particle enhanced immunoturbidimetric assay¹¹ (CRPL3; Roche Diagnostics) was used for the CRP analysis, with a detection limit of 0.3 mg/L and an extended measuring range of 0.3–350 mg/l, and was performed on a CP3000™ analyzer (Sekisui Medical, Tokyo Japan).

2.1

2.1 Surgical technique

All patients underwent measured resection performed by the same surgeon. The implants used were a NexGen CR-Flex (Zimmer-Biomet. Inc., Warsaw, IN) in 4 patients and a Journey 2 Bi-Cruciated Stabilized Knee System (Smith & Nephew. Inc. Memphis, TN) in 42 knees. The anesthesia method was a combination of conduction anesthesia (femoral nerve and sciatic nerve block) and general anesthesia. Compression stockings and a foot pump were used during surgery to help prevent DVT, and a suction drainage was attached. From a day after TKA, the patients were allowed to walk without continuous passive motion. D-Dimer and FDP levels were measured at 1, 2, 5, 9, 12, 16 19, 23, 26, and 30 days after TKA. The treatment algorithm of anticoagulation at our institute after TKA is shown in Fig. 2. Enoxaparin sodium started from a day after TKA, and lower limb venous echocardiography was performed at 9 and16 days after TKA. Subcutaneous heparin calcium, intravenous heparin, or novel oral anticoagulant (NOAC) was selectively administered.

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Fig. 2 Flow diagram of anticoagulant therapy after total knee arthroplasty at our institute.

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3 Results

No significant difference was observed in age, gender, body weight, height, Knee Society Score, and range of motion between the two groups before TKA (Table 1). There was no significant difference about operation time between the two groups (The average operating time: Group A: 72.7 min, Group B: 78.9 min). The most delayed days of negative CRP conversion were 96 days in Group A and 19 days in Group B after TKA. The maximum value of D-Dimer after TKA was 30.2 μg/ml in Group A and 18.7 μg/ml in Group B. The maximum value of FDP after TKA was 68.2 μg/dl in Group A and 42.1 μg/dl in Group B (Table 2).

D-Dimer values for Group A were significant higher than Group B at 30 days after TKA (p = 0.011, F = 3.053. Table 3). FDP values for Group A were significant higher than Group B at 30 days after TKA (p = 0.002, F = 4.216. Table 4).

The ROC analysis of D-Dimer values at 30 days after TKA yielded an AUC of 0.891 (95% confidence interval (CI) 0.858–1.000), which indicates nearly an excellent test. The cutoff point of 22.1 μg/dl for FDP value (Younden Index: 22.1 μg/dl) showed a sensitivity of 81.8% (95% CI 70.1–92.8) and a specificity of 80.0% (95% CI 67.9–89.1) (Table 5).

4 Discussion

To our knowledge, this is the first study to evaluate the role of serum FDP assessment as a factor for CRP negative conversion. Greidanus et al.¹⁵ reported that patients with a CRP level ≥13.5 mg/dl after TKA are more likely to develop PJI; therefore, removal of prosthesis and debridement may be required. However, in the present study, we confirmed that CRP values of patient with an FDP level ≥22.1 μg/dl at 30 days after TKA necessarily showed negative conversion without antibiotic administration, when examining a patient with elevated serum CRP of minor criteria in the definition of PJI proposed by MSIS (other criteria do not apply).

The diagnosis of PJI has challenged surgeons since the advent of joint arthroplasty.¹⁶ Windisch C et al.³ reported that neither the absolute potential postoperative CRP value nor its course in the first 5 days after TKA is suitable for detecting an early infection: however, as in present case, we experienced a case of CRP negative conversion after TKA. There are several reasons for this diagnostic difficulty, including the absence of specific clinical signs and symptoms, the relative lack of accurate laboratory tests,^17–19 while Vanderstappen C et al. revealed that intra-articular and serum CRP analysis showed a very high diagnostic strength of PJI²⁰: therefore, we plan to investigate correlation between intra-articular CRP analysis and FDP value.

There is evidence that preoperative CRP levels provide a predictive factor for infection after TKA and are an important tool of diagnosing PJI.^21–23 In this study, preoperative CRP levels were normal values in 46 knees.

D-Dimer and FDP assessment results in fibrinolytic activities.^24–26 Recently, Shahi A et al.⁹ found that serum D-Dimer is a promising marker for the diagnosis of PJI, and Rodelo JR et al.²⁷ reported that higher levels of D-Dimer were associated with increased 28- day mortality in patients with sepsis and emphasized the prognostic role of D-Dimer among septic patients. In the future, serum FDP analysis may have a strength for PJI diagnosis.

A first weakness of our study is that this was a retrospective study and certain values were missing owing to the absence of a standardized prospective study protocol. Next weakness is that the inadequate number of cases was assessed and patients with PJI and VTE after TKA were excluded. A third weakness of this study is that the parameters of this study are only standard hospital serum D-Dimer and FDP assay. A fourth weakness of this study is that according to MISIS definition of PJI, both ESR and CRP need to be elevated, however we did not measure and assess ESR in the present study. The last weakness of this study is that the groups were divided between the two based on 20.3 days, the mean duration of hospitalization after TKA in our institute.

5 Conclusions

The present study provided that CRP values of patient with an FDP level ≥22.1 μg/dl at 30 days after TKA necessarily showed negative conversion without antibiotic administration, when examining a patient with elevated serum CRP of minor criteria in the definition of PJI proposed by MSIS.

Abbreviations

PJI: Periprosthetic joint infection; TKA: Total knee arthroplasty; CRP: C- reactive protein; MSIS: Musculoskeletal infection society; VTE: Venous thromboembolism; FDP: Fibrin degradation product; ROC: Receiver operating characteristic; AUC: As the area under the curve.

Funding

The study was not funded.

Availability of data and materials

The datasets used and/or analyses during the current study are available from the corresponding author on reasonable request.

Authors' contributions

TK and TF designed the study and wrote the manuscript. TS, HI and YM evaluated the data. All authors approved the final manuscript.

Ethics approval and consent to participate

The present study followed the Declaration of Helsinki and was approved by the local ethics committee of the Toho University Ohashi Medical Center, Tokyo, Japan.

Consent for publication

No applicable.