Plasma Fibrinogen is a good new auxiliary diagnostic marker for periprosthetic joint infection

Background: To test the meaning of serum CRP, ESR, Platelet Count and Mean Platelet Volume ratio (PC/MPV), plasma Fibrinogen and D-Dimer in periprosthetic joint infection diagnosis (PJI). Methods: Clinical data of 149 patients diagnosed with osteoarthritis (Group A), PJI (Group B) and aseptic loosening after joint arthroplasy (Group C) were retrospectively studied. General data and preoperative serum CRP, ESR, Platelet Count and Mean Platelet Volume ratio (PC/MPV), plasma Fibrinogen and D-Dimer levels were analyzed. The sensitivity and specicity of serum CRP, ESR, Platelet Count and Mean Platelet Volume ratio (PC/MPV), plasma Fibrinogen and D-Dimer in PJI diagnosis were compared. Results: Expression level of serum CRP, ESR, PC/MPV and plasma Fibrinogen in Group B are higher than Group A and C. Expression level of plasma D-Dimer in Group B are higher than Group A but similar with Group C. When PC/MPV>31.70, plasma Fibrinogen > 4.01 μg/mL and plasma D-Dimer > 1.17 mg/L were set as the threshold value for the diagnosis of PJI, the sensitivity of PC/MPV in PJI diagnosis is lower than ESR and Plasma Fibrinogen. Whereas, there are no statistically signicant differences when compared specicity of serum CRP, ESR, PC/MPV, plasma Fibrinogen and D-Dimer in PJI diagnosis. Conclusion: PC/MPV and plasma D-Dimer should not be used as the rst screen markers for PJI diagnosis, whereas, the plasma Fibrinogen can be used as a new auxiliary marker for PJI diagnosis.


Background
Periprosthetic joint infection (PJI) is still the most terrible complication for both patients and clinical surgeons. Although one stage or two stage revision surgery combined with antibiotics treatment exert favorable clinical effect in PJI patients, it is not easy for clinicians to make an accurate PJI diagnosis in some situations due to the absence of a gold standard for PJI diagnosis [1,2]. Owing to the low-risk and rapidity of blood test, it is always selected by clinicians as the rst examimation for PJI diagnosis. Despite serum CRP and ESR are recommended as the diagnostic criteria by Musculoskeletal Infection Society (MSIS) [3] and commonly checked for PJI diagnosis [3], they do not work well in situations including chronic [4] and low virulence organism infections [1,2]. In the past a few years, the meaning of numerous blood markers such as serum soluble intercellular adhesion molecule-1 (sICAM-1) [5], myeloidrelated protein14  [6], soluble urokinase plasminogen activation receptor (su-PAR) [7] and lipopolysaccharide-binding protein (LBP) [8,9] have been tesetd in PJI diagnosis, . Although some of these markers showed good performance in PJI diagnosis, due to high expense and special antibodies, it is not possible to prevail them in clinical practice especially in primary hospitals in the near a few years.
So, it is emergent for us to explore some new convenient, and e cient blood markers for PJI diagnosis.
Coagulation and in ammation theory, which means excessive activation of coagulation could indicate the status of infection and in ammation, has been used in infection and in ammation diseases diagnosis for a long time [10,11]. However, the relationship between PJI and coagulation is still unclear.
Recently, the sensitivity and speci city of several coagulation markers including D-Dimer [12][13][14] Platelet Count and Mean Platelet Volume ratio [15] and plasma Fibrinogen [16] were compared with CRP and ESR in PJI diagnosis, and these studies showed that these commonly used coagulation markers can be selected for PJI diagnosis. However, no subsequent studies were published thereafter. And whether these markers could be used for PJI diagnosis is still unclear. As these blood markers were commonly used in clinical practice, the diagnostic value of these markers in PJI diagnosis deserved our exploration.
In this study, we rechecked and evaluated the meaning of serum CRP, ESR, Platelet Count and Mean Platelet Volume ratio PC/MPV , plasma Fibrinogen and D-Dimer in PJI diagnosis, and demonstrated that PC/MPV and plasma D-Dimer should not be used as the rst screen markers for PJI diagnosis, whereas, the plasma Fibrinogen can be used as a new auxiliary marker for PJI diagnosis.

Study population
Patients diagnosed with primary osteoarthritis, PJI and aseptic loosening in our department have the data of preoperative serum CRP, ESR, Platelet Count and Mean Platelet Volume ratio PC/MPV , plasma Fibrinogen and D-Dimer expression level from July 2016 to December 2019 were included. Exclusion criterion can be seen in our previous published paper [17].
De nition of PJI and aseptic loosening PJI was de ned using the MSIS criteria [3]. Aseptic loosening was de ned using the criteria in our previous published paper [17].

General Information of Participants
This study was conducted in accordance with the Dec-laration of Helsinki (Ethical Principles for Medical Research Involving Human Subjects) and was approved by ethics board of Henan Provincial People's Hospital.
From July 2016 to December 2019, we collected 232 clinical data of patients diagnosed with primary osteoarthritis, PJI and aseptic loosening in our department. Finally, 83 patients were excluded and 149 patients (103 female and 46 male) were included in the study.

Statistical Analysis
Quantitative data were recorded as mean ± standard deviation, single factor analysis of variance was selected for comparison difference among multiple groups and SNK test was selected for comparison between any two means. Chi-square test (c 2 ) was selected for comparison the counting data among groups. P value less than 0.05 was considered as signi cant difference. If the difference is signi cant partition of chi-squareis used for comparison between any two means and P value less than 0.017 was Page 4/10

Included population
In this study, 149 patients were included and grouped as following: Group A: 64 primary osteoarthritis patients (received primary arthroplasty); Group B: 47 PJI patients (received resection arthroplasty and antibiotic-cement spacer insertion surgery); Group C: 38 aseptic loosening patients (received revision surgery). Patient demographics are presented in Table 1 and there were no signi cant differences among the three groups.  As shown in Table 3, the sensitivity of plasma Fibrinogen is similar with CRP and ESR, while the sensitivity of PC/MPV is lower than CRP and ESR. However, when the speci city of serum CRP, ESR, PC/MPV and plasma Fibrinogen in PJI diagnosis were compared among patients from three different groups, the differences are not statistically signi cant (Table 4). All these data indicate that plasma Fibrinogen can be used as a new marker for PJI diagnosis, while, PC/MPV should not be used as a new marker for PJI diagnosis.

Discussion
Considering the great success of joint arthroplasty, the number of patients receiving joint arthroplasty has increased year by year. At the same time, researchers estimated that the incidence of Hip and Knee Arthroplasty revision surgery in the United States is projected to increase to 2030 [18]. In 2017, papers published by Delanois et al and Gwam et al showed that PJI is the most common reason for revision in total knee arthroplasty patients [19] and the fourth most common reason for revision in total hip arthroplasty patients in the United States [20]. Although one stage or two stage revision surgery combined with antibiotics treatment exert excellent clinical effect, it is still not easy to make a prompt and accurate PJI diagnosis, PJI diagnosis remains challenging.
Despite numerous efforts have been tried to increase the accuracy of PJI diagnosis, until now, there is still no consensus on the superiority of one method better than another. Compared with other methods, blood examination, which has the merit low-risk, non-invasion and rapidity, is always the rst screening option for clinicians to make a PJI diagnosis. Though CRP and ESR are still widely used as rst-line screening markers for PJI, they are non-speci c blood in ammatory markers and could be in uenced by many factors [21]. So, lots of researchers are trying to evaluate the meaning of some other blood markers in PJI diagnosis.
Despite coagulation markers such as Platelet Count and Mean Platelet Volume ratio [22], D-Dimer [23] and plasma Fibrinogen [24] have been used in in ammation and infection diseases diagnosis [10,11], the role of these coagulation markers in PJI diagnosis is still unknow. Although the role of D-Dimer [12][13][14] plasma showed that plasma D-dimer has limited performance for the diagnosis of PJI. As a result, our conclusion performs better than Paziuk et al's and Qin et al's in clinical utilization. However, there are several limitations in our study: 1, the number of included patients in our study is only 149, much lesser than Paziuk's (4938 patients), which indicates our conclusion is less reliable than Paziuk's to some extent; 2, we also excluded those have rheumatologic disease, which constitute almost 10% patients in our department, which to some extent limited the practicability of our conclusion in clinical PJI evaluation.

Conclusions
Overall, in this study, different from previous studies, which focused on in ammatory markers other than coagulation-related indicators in PJI diagnosis, we found that the plasma Fibrinogen can be used for as a new marker for PJI diagnosis.