Moderate strength evidence does not support the clinical utility of the following to aid in the diagnosis of PJI:

• Peripheral blood leukocyte count
• Serum tumor necrosis factor-a

Rationale
There were two high quality studies, eight moderate and one low quality study evaluating serum ESR (Della Valle 2007; Greidanus 2007; Alijanipour 2013; Bottner 2007; Buttaro 2010; Cipriano 2012; Elgeidi 2014; Kamme 1981; Savarino 2004; Schinsky 2008; Kwon 2016).

There were two high quality studies, eleven moderate and one low quality article evaluating serum CRP (Della Valle 2007; Greidanus 2007; Alijanipour 2013; Bottner 2007; Buttaro 2010; Cipriano 2012; Elgeidi 2014; Fernandez-Sampedro 2017; Fink 2008; Fink 2013; Savarino 2004; Schinsky 2008; Yuan 2015; Kwon 2016).

If both ESR and CRP were negative, the combined tests were strong at ruling out PJI (negative LR=0 to .06). If both tests were positive, the tests were also useful for ruling in PJI (positive LR range=4.34 to 13.5).

There is concern that ESR and CRP may be elevated in the early postoperative period, which could affect the reliability of these tests. Three included studies evaluated these biomarkers for PJI in the early postoperative period. A moderate quality study by Fernandez-Sampedro (2017) found CRP (13.5mg/L) to be a weak test for diagnosing PJI in hip and knee patients within 3 months of surgery (positive LR=3.52; negative LR=0.24), with the test result producing a small (but sometimes important) change in probability PJI. Another moderate quality study (Alijanipour 2013) of hip and knee patients showed CRP (23.5mg/L) to be a strong rule in test (positive LR=14.5), and moderately good rule out test (negative LR=.14) within 4 weeks of surgery. The same study found that ESR (54.5 mm/hr) was a strong rule in test (positive LR=11.4), but a weak rule out test (Negative LR=.21) for early PJI. Finally, a low-quality study of hip patients by Yi (2014) found ESR (44 mm/hr) was a moderately good rule out test within six weeks of surgery but was poor for ruling in PJI (positive LR=1.96; negative LR=.15). The same study found CRP to be a strong rule in test (positive LR=66.76) and a moderate rule out test (negative LR=.12), although it should be noted that the positivity threshold of 93 mg/L was much higher than the other CRP studies in this recommendation.

Another concern is that ESR and CRP tests could be elevated by other inflammatory conditions. Cipriano (2012) evaluated ESR (30mm/hr) and CRP (17 mg/L) in hip and knee patients with inflammatory arthritis. ESR was a weak rule in test (positive LR=2.34), indicating that a positive test produced a small, but sometimes important change in probability of PJI. However, a negative ESR test strongly decreased the probability of PJI (negative LR=.09). CRP also was a weak rule in test, but a strong rule out test (positive LR=3.32; negative LR=.07). Kwon (2016) evaluated ESR (22mm/hr) and CRP (31.3mg/L) in hip patients with dual taper modular implants who underwent revision for adverse local tissue reaction due to taper corrosion. ESR was a strong rule in test in these patients (positive LR=10.48) but was a weak rule out test (negative LR=.45). CRP was a weak rule in test (positive LR=3.93) and a poor rule out test (negative LR=.77).

One moderate quality hip study (Buttaro 2010) and two moderate quality hip/knee studies (Bottner 2007; Elgeidi 2014) evaluated serum IL-6. IL-6 was a moderately strong rule-in test (positive LR range=7.03 to 9.67) and may be useful as a rule-out test (negative LR=0-.67). 

In arthroplasty failure, it is important to distinguish PJI from non-infectious causes because the surgical and medical management varies. Blood is easy to collect, and a number of biomarkers can be tested. Some are useful for PJI diagnosis, whereas others are not. Of the listed biomarkers, only ESR and CRP are commonly performed and have strong evidence supporting their use. Serum interleukin-6 has been studied in a smaller number of studies and its use is supported, though it is not widely available, and what it adds to ESR and CRP, which are more commonly performed, has not been defined. Conversely, moderate evidence supports not using tumor necrosis factor-a or peripheral blood leukocyte count for PJI diagnosis, because they were poor at ruling out PJI (Bottner 2007; Elgeidi 2014; Savarino 2004; Spangehl 1999; Yuan 2015; Claassen 2016; Trampuz 2007).

POSSIBLE HARMS OF IMPLEMENTATION
Neither CRP nor ESR is perfectly accurate for PJI diagnosis. These biomarkers may be elevated as a result of inflammatory conditions not related to PJI; conversely, they are not always positive in cases of PJI. Therefore, they should not be used as the sole tests to diagnose PJI. None of the listed biomarkers defines the microbiology of PJI, which is important to inform appropriate management.

FUTURE RESEARCH
As noted in the subsequent recommendation, the goal of testing for PJI is to rule in or rule out this diagnosis. No test should be used alone. In most cases, a diagnosis can be achieved without using all of the testing listed, and testing should be deployed in an algorithmic fashion; defining such an algorithm is beyond the scope of this guideline. Novel blood-based biomarkers, including procalcitonin, are currently being explored. The relative value of biomarker testing (e.g., CRP, interleukin-6) on serum versus synovial fluid remains to be defined.
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