Serological Markers of Infection in the Infected Total Knee Arthroplasty

MSIS definition of PJI
PJI exists when:


There is a sinus tract communicating with the prosthesis


A pathogen is isolated by culture from two or more separate tissue or fluid samples obtained from the affected prosthetic joint


When four of the following six criteria exist:

(a) Elevated serum erythrocyte sedimentation rate and serum C-reactive protein (CRP) concentration

(b) Elevated synovial white blood cell count

(c) Elevated synovial polymorphonuclear percentage (PMN%)

(d) Presence of purulence in the affected joint

(e) Isolation of a microorganism in one culture of periprosthetic tissue or fluid

(f) Greater than five neutrophils per high-power field in five high-power fields observed from histologic analysis of periprosthetic tissue at ×400 magnification

Table 9.2
ICM definition of PJI [6]

ICM definition of PJI
PJI is present if one of the two major criteria or three of five minor criteria exists

Major criteria

1. There is a sinus tract communicating with the prosthesis

2. Two positive periprosthetic cultures with phenotypically identical organisms

Minor criteria

Having three of the following minor criteria:

Acute PJI (<90 days)

Chronic PJI (>90 days)
1. Elevated ESR or CRP

ESR: no threshold

ESR: >30 mm/h

CRP > 100 mg/L

CRP > 10 mg/L
2. Elevated SF WBC count

10,000 cells/μL

3000 cells/μL
 Changes in leukocyte esterase strip

+ or ++

+ or ++
3. Elevated SF PMN %


4. Positive histologic analysis of the periprosthetic tissue

>5 neutrophil per high-power field in 5 high-power fields (×400)

>5 neutrophil per high-power field in 5 high-power fields (×400)
5. A single positive culture

9.2 Serum Biomarkers

In 1998, the National Institutes of Health defined a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic response to a therapeutic intervention.” Biomarkers represent the most objective reproducible medical signs [8]. Serum markers can be used as screening tools, in combination with other serum markers to support a diagnosis, to monitor response to therapy. The following section will examine the serum biomarkers involved with PJI diagnosis. Each serum marker will be discussed individually to explain their genesis, purpose, power, and limitations.

9.2.1 Traditional Serum Biomarkers

Routine workup for PJI involves the measurements of serum white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). WBC Count

Serum white blood cell (WBC) count is used as a proxy to measure a host response to infection [9]. Serum WBC count and neutrophil differential are frequently ordered in the workup of suspected PJI; however, several studies have shown limited efficacy (minimal role) in the diagnosis of PJI [1012]. A meta-analysis that pooled studies related to serum WBC count found its sensitivity to be 45% and specificity to be 87% in diagnosis of PJI [13]. Furthermore, WBC count is influenced by antibiotic use and can be low in patients who are immunosuppressed or high in patients with hematologic malignancies.

Recommendation: Due to its low sensitivity, WBC count is not recommended for the diagnosis of PJI. Erythrocyte Sedimentation Rate

Erythrocyte sedimentation rate (ESR) is the time at which red blood cells (RBCs) in a test tube separate from blood serum and settle at the bottom of the tube. The sedimentation rate increases with inflammation. ESR is a nonspecific measurement of inflammation and tissue injury and has been found to be elevated from 3 to 12 months following surgery, but on average remains elevated for the acute postoperative period (6 weeks) [14, 15].

Current guidelines recommend the use of ESR in conjunction with CRP as a first-line screening test for the diagnosis of PJI. At the international consensus meeting (ICM) in 2013, no threshold was established for ESR during the acute postoperative period as ESR is not useful in the diagnosis of acute PJI [6]. However, ESR can be used for patients with chronic PJI. For chronic PJI (greater than 6 weeks), the ICM did deem an ESR of greater than 30 mm/h as an appropriate threshold to aid in the diagnosis of chronic PJI [46]. A meta-analysis showed a pooled sensitivity of 75% and specificity of 70% for ESR in diagnosis of PJI [13]. ESR is a marker for inflammation and thus can be elevated by other concomitant systemic diseases such as: renal disease, malignancy, chronic inflammatory conditions, advanced age, gender, and others [16]. In addition, ESR can be influenced by immunosuppression and premature antibiotic therapy as with many of the serum biomarkers discussed below. Lastly, the method by which ESR is measured, manual versus automated, also affects the results [1719]. In recent years the manual method of ESR measurement (Westergren method) has been abandoned in favor of automated count, making reference to the threshold to the ESR value in the old literature less relevant. C-Reactive Protein

C-reactive protein (CRP) is an acute-phase protein synthesized in the liver that functions to activate the complement system. CRP levels rise rapidly in the postoperative period, normalizing by 2–4 weeks [20]. Unlike ESR, CRP can be used for the diagnosis of both acute and chronic PJI. At the ICM in 2013, a threshold of greater than 100 mg/L (for the knee and hip) was recommended for CRP during the acute postoperative period for the diagnosis of acute PJI [6, 21]. For chronic PJI (greater than 6 weeks), the ICM did deem a CRP threshold of greater than 10 mg/L as appropriate to aid in the diagnosis of chronic PJI [46].

A meta-analysis showed a sensitivity of 88% and specificity of 74% for CRP in diagnosis of PJI. Although more specific than ESR, CRP can also be found to be elevated in any inflammatory condition such as inflammatory arthropathies, infections, and neoplasia [13]. Further, the level of serum CRP may be affected by premature antimicrobial therapy and immunosuppression [22].

It should be noted that the ICM has come to a consensus on the diagnostic threshold values of PJI for ESR and CRP in both the acute and chronic postoperative period; however, individual studies have reported differing threshold values, particularly in the setting of acute infections. One study reported thresholds for acute postoperative period of 54 mm/h for ESR and 23.5 mg/L for CRP. The same study reported on thresholds of 46.5 mm/h for ESR and 23.5 mg/L for the chronic postoperative period [23]. Erythrocyte Sedimentation Rate and C-Reactive Protein

ESR and CRP are inexpensive, widely available, and noninvasive diagnostic tests. In combination, ESR and CRP have proven to be a valuable screening test with a combined sensitivity of 98% for the diagnosis of PJI [24, 25].

In 2010, the AAOS issued several guidelines with respect to the diagnosis of PJI. The AAOS strongly recommended ESR and CRP testing for patients assessed for PJI. Following abnormal ESR and/or CRP results, the AAOS also strongly recommends that the knee be aspirated, with aspirated fluid to be sent for microbial culture and synovial fluid WBC count and differential. For abnormal ESR and/or CRP results in the hip, AAOS strongly recommends a selective approach toward aspiration based on the probability of PJI and planned reoperation status [26].

More recently, the AAOS has recommended the combination of ESR and CRP tests to “rule out” infection. When both ESR and CRP are negative, PJI is unlikely (negative likelihood ratio 0–0.06). When both ESR and CRP are positive, PJI must be considered (positive likelihood ratio 4.3–12.1). Through the analysis of several level I studies that examined the use of ESR, CRP, and the combined use of ESR and CRP, the AAOS has concluded that the use of either test alone is less reliable in “ruling out” or “ruling in” infection as compared to when both tests are combined. Given the “rule out” reliability of the combined use of ESR and CRP, aspiration should be considered if ESR and CRP values are abnormal or if clinical suspicion is very high [26].

While ESR and CRP are currently the “gold standard” in the diagnosis of PJI, they are not without limitations. Following revision surgery, both ESR and CRP cannot reliably predict the persistence or elimination of infection [27, 28]. Several studies have reported that ESR and CRP have limited efficacy in predicting eradication of infection and determining the optimal timing for reimplantations. Furthermore, because ESR and CRP are affected by systemic diseases, they have limited efficacy in diagnosing PJI in patients with inflammatory arthropathies, a common etiology for end-stage arthritis requiring arthroplasty. Additionally, both tests have a limited ability in the setting of premature antimicrobial administration and low sensitivity for detecting low-virulence organisms such as coagulase-negative Staphylococcus, Propionibacterium acnes, Candida, Corynebacterium, Mycobacterium, and Actinomyces [29].

Recommendation: The combination of ESR and CRP is an effective diagnostic tool to “rule out” PJI ( Table 9.3 ).

Table 9.3
This table shows the effectiveness of combination of ESR and CRP to rule out PJI


Sensitivity, %

Specificity, %



WBC count




Not recommended




Acute PJI: none

Chronic PJI: >30 mm/h

Recommended as screening test




Acute PJI: > 100 mg/L

Chronic PJI: >10 mg/L

Recommended as screening test


Recommended as screening test

9.2.2 Ancillary Serum Biomarkers IL-6

Interleukin-6 (IL-6) is a pro-inflammatory cytokine produced by stimulated monocytes and macrophages. IL-6 is a major regulator of the acute-phase response, stimulating the secretion of other acute-phase proteins including CRP. This means that IL-6 has a faster response to infection and provides an opportunity for early detection of PJI [30]. In normal individuals, serum IL-6 level is approximately 1 pg/mL but can increase to 30–430 pg/mL for up to 3 days following total joint arthroplasty [10, 31]. IL-6 values peak at two days after uncomplicated arthroplasty before rapidly returning to normal values [13].

Studies have shown IL-6 to have a PJI diagnostic odds ratio of 28.6 compared with 7.1 for CRP. The combination of IL-6 and CRP improved the diagnostic odds ratio to 168 [32]. One study reported IL-6 to have a sensitivity of 46.7% and specificity of 95% for the diagnosis of PJI [33]. A meta-analysis showed a pooled sensitivity of 97% and specificity of 91% [13].

Recommendation: IL-6 has shown promise in the early detection of PJI with its faster response to infection. IL-6 is currently not used widely or part of consensus guidelines, but the literature supports its efficacy in the diagnosis of PJI. More investigation is required to validate routine use of IL-6.

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Mar 10, 2018 | Posted by in ORTHOPEDIC | Comments Off on Serological Markers of Infection in the Infected Total Knee Arthroplasty
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