Combination of C-reactive protein and fibrinogen is useful for diagnosing periprosthetic joint infection in patients with inflammatory diseases : Chinese Medical Journal

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Original Articles

Combination of C-reactive protein and fibrinogen is useful for diagnosing periprosthetic joint infection in patients with inflammatory diseases

Xu, Hong1; Xie, Jinwei1; Wan, Xufeng1; Liu, Li2; Wang, Duan1; Zhou, Zongke1

Editor(s): Yin, Yanjie; Hao, Xiuyuan

Author Information
doi: 10.1097/CM9.0000000000002215

Abstract

Introduction

Inflammatory diseases such as rheumatoid arthritis,[1] ankylosing spondylitis,[2] psoriatic arthritis,[3] systemic lupus erythematosus (SLE),[4] and gouty arthritis [5] are characterized by high levels of inflammatory cytokines in the body. Patients with inflammatory diseases are at significantly higher risk of total joint arthroplasty (TJA) than healthy individuals due to their use of glucocorticoids and the continuous stimulation of inflammatory cytokines in the joints.[6] Patients with inflammatory diseases are also at higher risk of periprosthetic joint infection (PJI) after TJA.[7,8] These infections lead to higher hospitalization expenses, longer hospital stays, and more disabilities, even mortality, especially if they are not diagnosed before undergoing revision hip or knee arthroplasty.[9] Hence, reliable biomarkers are needed for the early screening of infection in patients with inflammatory diseases.

Blood markers are easily accessible and therefore play a significant role in the screening of PJI.[10] The International Consensus Group has introduced several inflammatory biomarkers for screening of infection before revision hip or knee arthroplasty, such as serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR).[11] However, their values in patients with inflammatory diseases remain unclear, as most studies have excluded or ignored these patients.[12] Furthermore, increased baseline values may be observed even in non-infected patients with inflammatory diseases,[13] which brings about the necessity to re-evaluate their current predictive cutoffs in these patients.

Plasma fibrinogen (FIB), monocyte/lymphocyte ratio (MLR), and neutrophil/lymphocyte ratio (NLR) are also strongly related to inflammation and infection.[14–17] So, they have been suggested as useful biomarkers for screening PJI before revision hip or knee arthroplasty.[18–20] However, it is unclear whether they are suitable indicators of infection in patients with inflammatory diseases prior to revision arthroplasty.

Therefore, in this retrospective study, we evaluated the ability of CRP and ESR for screening PJI in patients with inflammatory diseases prior to revision arthroplasty. In addition, we also evaluated the values of plasma FIB, MLR, and NLR alone and in combination for screening infection in these patients.

Methods

Ethical approval

The study was approved by the Ethics Committee of West China Hospital, Sichuan University (approval No. 2020–1004). The Committee waived the requirement for written informed consent, because the patient data remained anonymous and the study had no adverse effects on patient health. The study was registered in the Chinese Clinical Trial Registry (registration No. ChiCTR2000039989).

Study design

The retrospective study involved patients at our hospital with various inflammatory diseases, such as rheumatoid arthritis and ankylosing spondylitis, who underwent revision knee or hip arthroplasty due to infection or aseptic mechanical failure from January 2008 to September 2020. Patients who are not diagnosed with inflammatory diseases were excluded from the study. Patients who underwent revision arthroplasty due to periprosthetic fractures or joint dislocations were also excluded, because most such fractures or dislocations were caused by violent trauma rather than infection. Patients who underwent reimplantation arthroplasty were also excluded because of its complex source of pathogens and uncertain duration of infection.[21]

Diagnostic definition of infection and data extraction

In this retrospective study, infection was defined based on the 2013 the International Consensus Meeting (ICM) criteria.[11] According to these criteria, the patients involved in the study were divided into two groups: infected and non-infected.

Data on patients were collected from the electronic medical records of the hospital. Information was extracted based on the inflammatory diseases (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, SLE, gouty arthritis, Sjogren syndrome, or Still disease), sex, age, comorbidities (hypertension, diabetes, chronic obstructive pulmonary disease, and coronary heart disease), and Tsukayama type of PJI (type I is the infection diagnosed during or after revision procedure surgery, and the diagnosis before revision surgery is aseptic loosening for the infection sign is not obvious clinically; type II is the early post-operative infection; type III is the late chronic infection; while type IV is the acute hematogenous infection). Information was also extracted based on the laboratory test results, including ESR, serum CRP, plasma FIB, and counts of monocytes, neutrophils, and lymphocytes; the level of alanine transaminase (ALT) and aspartate amino transferase (AST); the results of culture tests of synovial fluid collected before and during surgery (see subsection “Laboratory evaluations”); as well as the pathology results of soft tissue around the prosthesis. MLR was defined as the ratio of monocyte and lymphocyte counts, while NLR was the ratio of neutrophil and lymphocyte counts.

Laboratory evaluations

Fasting venous blood samples were collected by nurses and examined in the hospital's laboratory on the day of collection from the patients.[10] ESR, serum CRP, and plasma FIB levels and monocytes, neutrophils, and lymphocytes counts were determined in blood assays. If infection was suspected based on the clinical signs such as pain and swelling, and the results of pre-operative CRP and ESR, the involved joint was aspirated pre-operatively, and the obtained synovial fluid was sent for tests as well as cultures with blood culture bottles. Besides, the synovial fluid of each patient was collected during surgery and sent for cultures. In addition, at least four soft tissues around the prosthesis were also collected from all patients during surgery and sent for tests as well as culture.

Sample size estimation

The area under the receiver operating characteristic curve (AUC) was used to estimate the minimal sample size with MedCalc 12.7 (MedCalc Software bvba, Ostend, Belgium). Previous studies reported the following AUCs for diagnosing PJI: 0.887 for CRP, 0.842 for ESR, 0.834 for plasma FIB,[19] 0.790 for MLR,[22] and 0.802 for NLR.[18] Thus, the minimal AUC of 0.790 for MLR along with a type I error (significance) of 0.05 and a type II error (1-power) of 0.10 were used to calculate the minimal sample size, which was determined to be 18 patients in each group.

Statistical analysis

Normally distributed quantitative variables were presented as mean ± standard deviation and assessed using Student's t test, while skewed data were described as median (interquartile range) and compared using the Mann-Whitney U test. The qualitative variables were showed as frequency (%) and assessed for significance using Pearson chi-squared test or Fisher's exact test between two groups.

Receiver operating characteristic curves were used to describe the relationship between true positive rate (sensitivity) and false positive rate (1–specificity) and to calculate the AUCs and their 95% confidence intervals. Besides, the positive predictive value and negative predictive value were also calculated. Optimal predictive cutoffs were determined for all tested markers using the Youden index. The diagnostic values of CRP and ESR were also evaluated with the cutoffs based on the 2013 ICM Criteria, 10 mg/L and 30 mm/h, respectively. All statistical analyses were performed using SPSS 24.0 software (IBM, Armonk, NY, USA).

Results

A total of 616 patients who underwent revision knee or hip arthroplasty due to infection or aseptic failure were initially considered for enrollment. After excluding patients without inflammatory diseases, and who underwent reimplantation and revision arthroplasty for periprosthetic fractures or joint dislocation, 62 patients with various inflammatory diseases were enrolled. Among them, 30 patients were diagnosed with infection and 32 without infection [Figure 1].

F1
Figure 1:
Flowchart of patient enrollment.

The most common inflammatory disease among the patients was rheumatoid arthritis, which was diagnosed in 21 (70.0%, 21/30) infected patients and 23 (71.9%, 21/32) in non-infected patients. The numbers, constituent ratios, and treatment of inflammatory diseases (ankylosing spondylitis, SLE, gouty arthritis, and psoriatic arthritis), Sjogren syndrome, and Still disease, as well as patients’ demographic characteristics and comorbidities are shown in Table 1. And the biomarkers of liver function including ALT and AST had no significant difference between the two groups. The characteristics including the planned operation, inflammatory diseases and pathogen of infection, medications use for the treatment of inflammatory diseases, Tsukayama type of PJI, and values of tested makers of the infected group are shown in Supplementary Table 1, https://links.lww.com/CM9/B106.

Table 1 - Characteristics of the patients who underwent revision knee or hip arthroplasty in infected and non-infected groups.
Variables Infected group (n = 30) Non-infected group (n = 32) P value
Inflammatory disease
 Rheumatoid arthritis 21 (70.0) 23 (71.9)
 Gouty arthritis 5 (16.8) 4 (12.5)
 Ankylosing spondylitis 1 (3.3) 1 (3.1)
 SLE 0 2 (6.3)
 Psoriatic arthritis 1 (3.3) 1 (3.1)
 Sjogren syndrome 1 (3.3) 1 (3.1)
Still disease 1 (3.3) 0
Whether to receive regular treatment recommended by their rheumatologist
 Yes 24 (80.0) 24 (75.0)
 No use 4 (13.3) 5 (15.6)
 Not reported 2 (6.7) 3 (9.4)
Demographic characteristics
 Age (years) 59.03 ± 13.72 59.89 ± 9.14 0.776
 Female 17 (56.7) 22 (68.8) 0.325
Comorbidities
 Hypertension 6 (20.0) 9 (28.1) 0.455
 Diabetes 1 (3.3) 2 (6.3) 1.000
 COPD 1 (3.3) 0 0.974
 CHD 0 1 (3.3) 1.000
Liver function
 ALT (U/L) 18.13 ± 6.54 19.47 ± 10.81 0.554
 AST (U/L) 22.00 ± 7.01 22.23 ± 7.94 0.641
Values are presented as n (%) or mean ± standard deviation.ALT: Alanine transaminase; AST: Aspartate amino transferase; COPD: Chronic obstructive pulmonary disease; CHD: Coronary heart disease; SLE: Systemic lupus erythematosus.

The levels of serum CRP, ESR, plasma FIB, and NLR were significantly higher in the infected group than in the non-infected group, while MLR did not differ significantly between the two groups [Table 2].

Table 2 - Tested markers in the infected and non-infected groups.
Potential markers Infected group (n = 30) Non-infected group (n = 32) P value
CRP (mg/L) 25.05 (17.80–63.33) 7.00 (4.09–19.40) <0.001
ESR (mm/h) 59.62 ± 30.77 44.31 ± 24.98 0.036
FIB (g/L) 4.36 ± 1.31 3.38 ± 0.76 <0.001
MLR 0.30 (0.22–0.39) 0.27 (0.18–0.37) 0.367
NLR 3.58 (2.86–5.93) 2.75 (2.04–3.96) 0.023
CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; FIB: Fibrinogen; MLR: Monocyte/lymphocyte ratio; NLR: Neutrophil/lymphocyte ratio.

The AUCs for CRP, ESR, FIB, and NLR were 0.813 (0.704–0.922), 0.638 (0.495–0.776), 0.795 (0.680–0.911), and 0.656 (0.518–0.794), respectively [Figure 2A and Table 3]. When the predictive cutoff of CRP was defined as 10 mg/L according to 2013 ICM criteria,[11] the sensitivity was 86.2% and specificity was 62.6%. However, based on the Youden index, the optimal predictive cutoff of CRP was 14.04 mg/L, which gave similar sensitivity of 86.2% but higher specificity of 68.7%. The sensitivity and specificity were 82.8% and 31.2%, respectively, when the predictive cutoff of ESR was defined as 30 mm/h according to the 2013 ICM criteria.[11] While the sensitivity and specificity were 62.1% and 56.2%, respectively, when its predictive cutoff was determined as 44.00 mm/h based on the Youden index. Interestingly, plasma FIB gave an unimpressive sensitivity of 72.4% but a high specificity of 78.3% with the optimal predictive cutoff of 4.04 g/L based on the Youden index [Table 3].

F2
Figure 2:
ROC curves. (A) CRP, ESR, FIB, MLR, and NLR on their own. (B) Combinations of two markers. (C) Combinations of three markers. (D) Combination of four markers. CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; FIB: Fibrinogen; MLR: Monocyte/lymphocyte ratio; NLR: Neutrophil/lymphocyte ratio; ROC: Receiver operating characteristic.
Table 3 - Diagnostic performance of the tested markers individually.
Potential marker AUC (95% CI) Youden index Predictive cutoff Sensitivity (%) Specificity (%) PPV (%) NPV (%)
CRP (mg/L) 0.813 (0.704–0.922) 0.487 10.00 86.2 62.6 68.3 82.7
0.549 14.04 86.2 68.7 72.1 84.2
ESR (mm/h) 0.638 (0.495–0.776) 0.140 30.00 82.8 31.2 53.0 65.9
0.183 44.00 62.1 56.2 57.1 61.3
FIB (g/L) 0.795 (0.680–0.911) 0.538 4.04 72.4 81.2 78.3 75.9
MLR 0.563 (0.415–0.710) 0.203 0.22 82.8 37.5 55.4 69.9
NLR 0.656 (0.518–0.794) 0.321 2.90 75.9 56.2 61.9 71.3
Predictive cutoffs determined based on the 2013 ICM criteria.
Predictive cutoffs determined based on the Youden index.95% CI: 95% confidence interval; AUC: Area under the receiver operating characteristic curve; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; FIB: Fibrinogen; ICM: International Consensus Meeting; MLR: Monocyte/lymphocyte ratio; NPV: Negative predictive value; NLR: Neutrophil/lymphocyte ratio; PPV: Positive predictive value.

Different combinations of the biomarkers including CRP, FIB, ESR, and NLR were also systematically evaluated for their effectiveness in PJI [Table 4]. Among the combinations of two biomarkers, the combination of CRP and ESR gave a sensitivity of 86.2% and a specificity of 68.7%, while combination of CRP and FIB gave a similar sensitivity of 86.2% and a higher specificity of 78.1% [Figure 2B]. The combinations of three biomarkers and all four markers were also evaluated; however, their diagnostic values did not significantly improve based on the combination of CRP and FIB [Figure 2C and 2D].

Table 4 - Diagnostic performance of the tested markers in combination.
Combination AUC (95% CI) Youden index Sensitivity (%) Specificity (%) PPV (%) NPV (%)
Combination of two markers
 CRP + ESR 0.815 (0.706–0.923) 0.549 86.2 68.7 71.6 84.0
 CRP + FIB 0.845 (0.741–0.949) 0.643 86.2 78.1 78.7 85.8
 CRP + NLR 0.814 (0.704–0.923) 0.549 86.2 68.7 71.6 84.0
 ESR + FIB 0.796 (0.681–0.911) 0.536 72.4 81.2 78.3 75.8
 ESR + NLR 0.702 (0.570–0.833) 0.354 44.8 90.4 81.4 63.6
 FIB + NLR 0.796 (0.682–0.911) 0.505 72.4 78.1 75.6 75.1
Combination of three markers
 CRP + ESR + FIB 0.846 (0.741–0.951) 0.674 86.2 81.2 81.1 86.3
 ESR + FIB + NLR 0.797 (0.683–0.912) 0.536 72.4 81.2 78.3 75.8
 FIB + NLR + CRP 0.851 (0.784–0.955) 0.674 86.2 81.2 81.1 86.3
 NLR + CRP + ESR 0.815 (0.706–0.923) 0.549 86.2 68.7 71.6 84.0
Combination of four markers
 CRP + ESR + FIB + NLR 0.850 (0.746–0.954) 0.706 86.2 84.4 83.8 86.7
95% CI: 95% confidence interval; AUC: Area under the curve; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; FIB: Fibrinogen; MLR: Monocyte/lymphocyte ratio; NPV: Negative predictive value; NLR: Neutrophil/lymphocyte ratio; PPV: Positive predictive value.

Discussion

The diagnosis of PJI is still challenging, especially for the patients with inflammatory diseases. The present study appears to be the first to evaluate the ability of plasma FIB, MLR, and NLR for screening PJI in patients with inflammatory diseases. Our results suggest that pre-operative CRP with a slightly higher optimal predictive cutoff and FIB are useful for screening PJI in patients with inflammatory diseases, and their combination may further improve their diagnostic values.

Serum CRP and ESR are effective for screening infection revision arthroplasty in patients without inflammatory diseases.[23,24] However, they may lead to high incidence of false-positive infection results in patients with inflammatory diseases, as they may be affected by various inflammatory factors.[25] Here we showed that serum CRP can efficiently diagnose infection in patients with inflammatory diseases. However, the predictive cutoff obtained based on the Youden index in our study (14.04 mg/L) was slightly higher than that introduced by 2013 CIM criteria (10.0 mg/L),[11] and it provided a higher specificity in our patients than the value recommended by International Consensus Group (62.6% vs. 68.7%). Shohat et al[13] also reported that the optimal cutoff of CRP for diagnosing PJI in patients with inflammatory arthritis is slightly higher than that without inflammatory arthritis (13 vs. 11 mg/L). The higher cutoff in patients with inflammatory diseases may be associated with higher baseline CRP levels. In a previous study,[19] patients with inflammatory diseases had higher mean CRP levels than those without such diseases, regardless of whether patients had PJI.

In contrast to CRP, ESR showed low specificity for screening of infection in patients with inflammatory diseases, based on the cutoffs recommended by the 2013 ICM criteria or obtained based on the Youden index. This result is inconsistent with the results of a previous study,[13] which reported a similar diagnostic ability and cutoff of ESR for patient with or without inflammatory diseases. This discrepancy may be related to differences in the use of disease-modifying anti-rheumatic drugs or glucocorticoids, and/or inflammatory stage. The combination of CRP and ESR also failed to improve the diagnostic value for screening infection in patients with inflammatory diseases in our study. Previous study reported that both CRP and ESR are useful for diagnosing PJI in patients with and without inflammatory arthritis, furthermore, their optimal cutoffs were also similar, 15 vs. 17 mg/L for CRP and 32 vs. 30 mm/h for ESR, respectively.[12] This discrepancy may be associated with the various stages of inflammatory activity and small sample size of their study which only included 19 patients with inflammatory arthritis in infected group.

FIB, an acute phase protein secreted by the liver and found in plasma, is known for its important role in thrombosis and hemostasis,[26] and it may also be involved in aseptic inflammatory diseases and infections.[15] High FIB levels have been associated with a higher risk of poor outcome in patients with COVID-19.[27] FIB is also an efficient biomarker for the detection of infection in patients with non-union of fractures after internal fixation, showing a sensitivity of 78.2% and a specificity of 82.4% at an optimal cutoff of 2.75 g/L.[28] In addition, FIB also is promising for predicting reinfection after debridement, antibiotics, and implant retention for both acute and chronic PJI, and it may perform better than CRP and ESR.[29] And it is also promising for screening PJI prior to revision arthroplasty in patients without inflammatory diseases.[19,30] The optimal cutoff values reported in those studies were 3.57 and 4.01 mg/L, respectively, and our study revealed that plasma FIB may be useful at an optimal cutoff of 4.04 mg/L for screening PJI in patients with inflammatory diseases subjected to revision arthroplasty. More importantly, its combination with CRP could improve the specificity compared with CRP alone.

The increase in MLR or NLR in peripheral blood is related to an increase in monocyte or neutrophil counts, while lymphocyte count is either unchanged or even decreased. During bacterial infection, monocytes and neutrophils, as primary effectors of innate immunity, usually proliferate to recognize and clear pathogens, while the number of lymphocytes decreases. Recent reports have indicated that MLR and NLR are promising for diagnosing community-acquired pneumonia.[14] NLR may have an advantage over other infection markers since its level can return to normal 4 days after total knee arthroplasty, significantly faster than the time required for ESR and serum CRP.[31] Indeed, NLR has proven to be a useful marker for the early screening of PJI after TJA with an optimal cutoff of 2.13 and an AUC of 0.802,[18] but whether those results also applied to patients with inflammatory diseases was not discussed. Here we found that NLR alone was not effective in the diagnosis of PJI in patients with inflammatory diseases, its combination with CRP also failed to give a higher diagnostic value than the combination of CRP and FIB.

After examining five blood markers alone and in combination, we conclude that the combination of CRP and FIB was useful for screening infection in patients with inflammatory diseases before revision arthroplasty, and the predictive cutoffs of CRP were slightly higher than that introduced by International Consensus Group.[11] Moreover, FIB is a routine biomarker tested pre-operatively for all patients to evaluate their coagulation function, which adds no additional cost for patients. Hence, it is therefore clear that our study provides an easily accessible and cost-effective strategy for screening PJI in patients with inflammatory diseases.

However, some limitations should also be considered such as the relatively small sample size. Studies with larger samples, preferably from multiple sites, should be performed to verify and extend our findings, especially the determination of the predictive cutoff of the potentially useful markers. Such studies should take into account additional factors, such as anti-rheumatic drugs or glucocorticoids use, surgical trauma and liver function, which may influence baseline levels of the candidate infection markers in patients with inflammatory diseases, thereby affecting the optimal predictive cutoff for the candidate markers.[32] Finally, the effect of surgical trauma, drug use, and liver function on the ability of serum CRP and plasma FIB for identifying PJI in patients with inflammatory diseases, as well as their optimal cutoffs should be determined with larger samples.

Conclusion

Our results suggest that pre-operative serum CRP with a slightly higher predictive cutoff and plasma FIB are useful for screening PJI in patients with inflammatory diseases, and their combination may further improve their diagnostic values. Studies with larger simple size are needed to verify our findings.

Acknowledgements

We thank A. Chapin Rodríguez, PhD, from Creaducate Enterprises Ltd. for editing the English text of a draft of this manuscript.

Funding

This work was supported by grants from the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. ZYJC18039) and the Sichuan University postdoctoral interdisciplinary Innovation Fund, and Post-Doctor Research Project, West China Hospital, Sichuan University (2020HXBH080).

Conflicts of interest

None.

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Keywords:

Periprosthetic joint infection; C-reactive protein; Fibrinogen; Diagnosis; Revision arthroplasty

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