Limited strength evidence supports that periprosthetic tissue nucleic acid amplification testing for bacteria is not useful in the diagnosis of PJI.

Rationale
Description of Evidence:
There was one high, five moderate and four low quality studies evaluating synovial fluid leukocyte count (Della Valle 2007; Cipriano 2012; Ghanem 2008; Trampuz 2004; Schinsky 2008; Spangehl 1999; Choi 2016; Higuera2017; Chalmers 2015; Kwon 2016). Seven studies obtained synovial fluid preoperatively, and three intraoperatively. There was one high, five moderate and three low quality studies evaluating synovial fluid neutrophil percentage (Della Valle 2007; Cipriano 2012; Ghanem 2008; Schinsky 2008; Spangehl 1999;Trampuz 2004; Balato 2017; Higuera 2017; Kwon 2016). Seven studies used fluid obtained preoperatively, and two used intraoperatively-collected fluid. Most of the studies found both tests to be moderate to strong at ruling in and ruling out PJI.

There were two high, seven moderate and one low quality studies evaluating the diagnostic accuracy of preoperative aspiration culture for bacteria (Della Valle 2007; Eisler 2001; Barrack 1993; Fink 2008; Fink 2013; Glithero 1993; Malhotra 2004; Mulcahy 1996; Williams 2004; Parvizi 2006). Every study evaluated preoperatively-collected synovial fluid, except the Parvizi 2006 study which used synovial fluid obtained operatively. A meta-analysis of the preoperative aspiration studies found it to be a good rule-in test [pooled positive LR=10.09 (6.74,15.09)]. Although slightly weaker as a rule-out, the test was still useful [negative LR=.29 (.22,.40)]. The intraoperatively-collected synovial fluid culture study found the test to be strong at ruling in, and moderately strong at ruling out PJI.

Three moderate quality studies evaluated the synovial fluid leukocyte esterase test (Koh 2017; Shafafy 2015; Parvizi 2011). Two studies used preoperatively-collected and one used intraoperatively-collected synovial fluid. The test was useful for ruling in (positive LR range=4.25 to 80) and ruling out PJI (negative LR range= 0 to .2). Three moderate and three low quality studies evaluated synovial fluid a-defensin testing (Kasparek 2016; Suda 2017; Bonanzinga 2017; Berger 2017; Deirmengian 2014; Bingham 2014). The strength of evidence is rated as moderate, although it is important to note that relevant conflicts of interest were present in five out of the six a-defensin studies. Three of the studies used synovial fluid obtained intraoperatively, and the other three used synovial fluid obtained preoperatively. The test was useful for ruling in (positive LR range=4.36 to 32.33) and ruling out PJI (.03 to .36).

One moderate and two low quality studies evaluated synovial fluid CRP using synovial fluid obtained preoperatively (Tetreault 2014; Omar 2015; Vanderstappen 2013). The positivity thresholds in these studies ranged from 1.8 to 14.1 mg/L. One additional moderate quality study used intraoperatively-collected synovial fluid for CRP in combination with leukocyte count and neutrophil percentage analysis (Sousa 2017). Synovial fluid CRP alone was a moderate to strong rule-in test and a moderate to strong rule-out test (positive LR range=5.86-15; negative LR range=0 to.19). When used in combination with synovial fluid leukocyte count or neutrophil percentage, it was very a strong rule-in test (positive LR range=39.88 to77.42), but a weaker rule-out test (negative LR=.23 to.4).

One moderate knee (Melendez 2016) and one moderate hip/knee study (Morgenstern 2017) evaluated synovial fluid PCR using synovial fluid obtained preoperatively. Morgenstern evaluated multiplex PCR and Melendez used a genus and group specific rapid PCR assay panel designed to target Staphylococcus species, Enterococcus/Granulicatella/Abiotrophia species, Proteus species, Enterobacteriaceae, Bacteroides fragilis group, Pseudomonas aeruginosa, streptococci, Corynebacterium species, Propionibacterium/Cutibacterium/Actinomyces species, and anaerobic Gram-positive cocci. PCR was moderately strong as a rule-in test (positive LR range=5.55-6.82), and was of use for ruling out PJI (negative LR range=0.45-0.48).

There were three high quality studies, six moderate and one low quality study evaluating histopathology (Della Valle 2007; Frances 2007; Ko 2005; Banit 2002; Boettner 2016; Fehring 1994; Kasparek 2016; Lonner 1996; Nunez 2007; Suda 2017). The studies used various thresholds, but most had positive likelihood ratios in the moderate to strong rule-in test range. There were enough studies to meta-analyze thresholds of at least 5 and 10 neutrophils/high powered field (HPF). Both meta-analyses revealed both thresholds were strong at ruling in PJI [(5 neutrophils/HPF LR+=13.82(7.29, 26.19); 10 neutrophils/HPF in 5 fields= 56.5(20.3,157.2)]. As rule-out tests, results were more inconsistent and were unable to be pooled, but indicated the test may be of some use for ruling out PJI (negative LR range=.05 to .91).

There was 1 high, 5 moderate and 1 low quality study that evaluated periprosthetic tissue cultures (Aggarwal 2013; Atkins 1998; Schafer 2008; Spangehl 1999; Trampuz 2006; Trampuz 2007; Parvizi 2006). A meta-analysis was conducted using a threshold of 2 or more positive samples, which was revealed to be a very good rule-in test [positive LR=28.9(14.3, 58.6)] and was somewhat useful as a rule-out test [negative LR=0.34(0.27, 0.43)].

One high and three moderate quality studies evaluated sonication fluid cultures (Greenwood-Quaintance 2014; Janz 2013; Trampuz 2006; Trampuz 2007) using various cutpoints for positivity. The studies, in general, found the test to be moderate to strong at ruling in PJI (positive LR=4.25 to 172.25, and to be useful as a rule-out test (Negative LR=.11 to .32). A meta-analysis was conducted which revealed an area under the curve of .90 (.87-.92).

One high and three low quality studies evaluated sonication fluid PCR (Greenwood-Quaintance,K.E., 2014; Cazanave 2013; Gomez 2012; Ryu,S.Y., 2014). The test was good at ruling in PJI (positive LR range=8.71-78.26) and was also useful for ruling it out (negative LR range=0.19-0.30). There was 1 moderate and one low quality study (Suda,A.J., 2017; Ryu,S.Y., 2014) evaluating periprosthetic tissue PCR. The test was weak at ruling in (positive LR range=2.92-4.84), but very poor at ruling out PJI (negative LR range=0.77-0.87).

Clinical Considerations:
It is important to distinguish PJI from non-infectious causes of arthroplasty failure because of divergent surgical and medical management. In addition, in cases of PJI, the infecting microorganism(s) should ideally be defined to direct antimicrobial therapy; only cultures and microbe-directed molecular diagnostics are able to define the infecting microorganism(s). Preferably, a diagnosis should be established pre-operatively to allow for pre-surgical planning. If feasible, preoperative arthrocentesis is recommended, with fluid submitted for leukocyte count and differential, as well as aerobic and anaerobic cultures. There are varying methods for performance of synovial fluid cultures; culture in blood cultures bottles may be helpful, although there is no United States Food and Drug Administration (FDA) approved/cleared system for this approach. No evidence supports routine fungal and mycobacterial cultures of synovial fluid.

It should be noted that interpretive criteria for synovial fluid leukocyte counts and differential vary from those applied to native joint septic arthritis, that some studies suggest that different cutoffs be applied for hip versus knee arthroplasties, and that cutoffs may vary with the time post-arthroplasty. Definition of appropriate cutoffs for synovial leukocyte count and differential are beyond the scope of this guideline.

Synovial fluid leukocyte esterase strip tests may be applied to synovial fluid as a rapid diagnostic for PJI, but no assay is United States FDA  approved/cleared for this indication and this testing may be redundant with leukocyte count and neutrophil percentage determination. Likewise, synovial fluid a-defensin and CRP may be used but are also not FDA approved/cleared at this time and may be redundant with leukocyte count and neutrophil percentage determination, and serum CRP, respectively. Several studies have examined microbial nucleic acid amplification tests (e.g., PCR) applied to synovial fluid; none of these tests are FDA-approved/cleared and this type of testing may be redundant with cultures and does not provide phenotypic susceptibility test results. In addition, not all nucleic acid amplification tests are equivalent. Some may target specific microorganisms (and not “all” PJI-causing organisms), whereas others may be more broad-range in nature, targeting, for example, a conserved bacterial gene (e.g., 16S ribosomal RNA gene).

If a preoperative diagnosis of PJI has been established and the microbiology defined, intraoperative testing for PJI may not be needed. Alternatively, if this is not the case, efforts should focus on determining whether or not the arthroplasty is infected and on defining the infecting microorganism(s). Histopathology is recommended, and when performed as frozen section histopathology, can provide a result during the operative procedure. Multiple periprosthetic tissues should be submitted for aerobic and anaerobic bacterial culture. Definition of the ideal number of periprosthetic tissues to be submitted to bacterial cultures is beyond the scope of this guideline. If implant components are being resected, they may be submitted for sonication, with aerobic and anaerobic bacterial cultures performed on the resultant sonication (or sonicate) fluid. No evidence supports routine fungal and mycobacterial cultures of periprosthetic tissues or sonication fluid. Several studies have examined microbial nucleic acid amplification tests (e.g., PCR) applied to periprosthetic tissues as well as sonication fluid; none of these tests is FDA-approved/cleared and this type of testing may be redundant with cultures and may be best reserved for culture-negative cases. One possibility to achieve this is to collect and reserve a sample for future molecular testing, if needed. The same caveats vis-à-vis lack of  equivalency between such tests as detailed for synovial fluid apply to nucleic acid amplification tests applied to periprosthetic tissues and sonication fluid.

Overall, sensitivity of nucleic acid amplification testing is better for sonication fluid than periprosthetic tissues.While nucleic acid amplification tests performed on periprosthetic tissue may be useful in ruling in PJI, they are not useful for ruling out PJI, and therefore not routinely recommended on this specimen-type. Swab cultures are not recommended because swabs sample a small amount of material, and alternative specimens, as detailed above, are easily collected, providing lower rates of false negative diagnoses.

POSSIBLE HARMS OF IMPLEMENTATION
There is no perfect test for diagnosis of PJI. Lack of sensitivity of the above-listed tests can lead to missed diagnoses and conversely, lack of specificity (either a false-positive diagnosis of PJI or detection of a microorganism which is not causing PJI) can lead to inappropriate surgery and/or use of unneeded antibiotics, increased cost of care, selection for antibacterial resistance, toxicity and/or dysbiosis. Additionally, not all test options are available at each center which may have resource, access to care, and cost implications not fully delineated in these recommendations.

FUTURE RESEARCH
While multiple tests are listed, the goal, as stated above, should be to rule in or rule out PJI and if ruled in, define its microbiology. In most cases, this can be achieved without using all of the testing covered. Ideally, testing should be deployed in an algorithmic fashion; defining such an algorithm is beyond the scope of this guideline but is needed. The field of molecular microbiology diagnostics, including organism-specific, multiplex panels, 16S ribosomal RNA gene or other broad-range bacterial PCR followed by Sanger sequencing of amplification products, targeted metagenomic sequencing and shotgun metagenomic sequencing, is rapidly developing, which will likely impact future recommendations. Future research should address the most appropriate type of advanced diagnostic(s), which specimen-types are ideal or such testing, the ideal number of specimens to be tested, and when, in the course of testing and under which scenarios this type of testing is most appropriate (i.e., develop algorithms for appropriate test utilization).
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