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Conventional Diagnostic Challenges in Periprosthetic Joint Infection

Nodzo, Scott R. MD; Bauer, Thomas MD, PhD; Pottinger, Paul S. MD; Garrigues, Grant E. MD; Bedair, Hany MD; Deirmengian, Carl A. MD; Segreti, John MD; Blount, Kevin J. MD; Omar, Imran M. MD; Parvizi, Javad MD, FRCS

JAAOS - Journal of the American Academy of Orthopaedic Surgeons: April 2015 - Volume 23 - Issue suppl - p S18–S25
doi: 10.5435/JAAOS-D-14-00385
Supplement Article
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Periprosthetic joint infection remains a clinical challenge with no benchmark for diagnosis. The diagnosis is based on many different clinical variables that may be difficult to interpret, especially in the setting of chronic systemic disease. Synovial fluid aspiration, diagnostic imaging, traditional culture, peripheral serum inflammatory markers, and intraoperative frozen sections each have their limitations but continue to be the mainstay for diagnosis of periprosthetic joint infection. As molecular- and biomarker-based technologies improve, the way we interpret and diagnose periprosthetic joint infection will ultimately change and may even improve diagnostic accuracy and turnaround time. Future research on this topic should be focused on improving diagnostic criteria for low-virulence organisms, improving interpretation of intraoperative frozen sections, and establishing improved synovial fluid and peripheral serum biomarker profiles for periprosthetic joint infection.

From the State University of New York at Buffalo, Department of Orthopaedics, Buffalo, NY (Dr. Nodzo), the Department of Pathology, Cleveland Clinic Foundation, Cleveland, OH (Dr. Bauer), University of Washington, Seattle, WA (Dr. Pottinger), Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC (Dr. Garrigues), the Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, MA (Dr. Bedair), the Department of Orthopaedic Surgery, The Rothman Institute, Philadelphia, PA (Dr. Deirmengian), Rush University Medical Center, Chicago, IL (Dr. Segreti), Northwestern University Feinberg School of Medicine, Chicago, IL (Dr. Blount and Dr. Omar), and The Rothman Institute, Thomas Jefferson University, Philadelphia, PA (Dr. Parvizi).

Dr. Nodzo or an immediate family member serves as an unpaid consultant to NanoAxis. Dr. Bauer or an immediate family member serves as a paid consultant to Stryker. Dr. Garrigues or an immediate family member is a member of a speakers’ bureau or has made paid presentations on behalf of Synthes and Tornier; serves as a paid consultant to Synthes and Tornier; has received research or institutional support from Arthrex, Tornier, and Zimmer; and has received nonincome support (such as equipment or services), commercially derived honoraria, or other non–research-related funding (such as paid travel) from DJ Orthopaedics and Zimmer. Dr. Deirmengian or an immediate family member is a member of a speakers’ bureau or has made paid presentations on behalf of Zimmer; serves as a paid consultant to Synthes, Zimmer, and Biomet; has stock or stock options held in Biostar Venture Fund, CD Diagnostics, Trice, and Domain; and has received research or institutional support from Zimmer and CD Diagnostics. Dr. Segreti or an immediate family member is a member of a speakers’ bureau or has made paid presentations on behalf of Merck, and has stock or stock options held in Pfizer. Dr. Parvizi or an immediate family member serves as a paid consultant to CeramTec, ConvaTec, Corentec, Johnson & Johnson, Medtronic, Smith & Nephew, TissueGene, and Zimmer; has stock or stock options held in Alphaeon, CD Diagnostics, Corentec, Hip Innovation Technology, Joint Purification Systems, and Physician Recommended Neutriceuticals (PRN); has received research or institutional support from 3M, Cempra, CeramTec, DePuy, the National Institutes of Health (National Institutes of Child Health and Human Development and National Institute of Arthritis and Musculoskeletal and Skin Diseases), the Orthopaedic Research and Education Foundation, Smith & Nephew, StelKast, Stryker, and Zimmer; and serves as a board member, owner, officer, or committee member of the Eastern Orthopaedic Association and the Muller Foundation. None of the following authors or any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Pottinger, Dr. Bedair, Dr. Blount, and Dr. Omar.

Infection rates of primary hip and knee joint arthroplasty have been reduced to 0.3% to 2% with modern aseptic techniques, but this rate may reach 20% in some revision procedures.1,2 Periprosthetic joint infection (PJI) can be disastrous, and a prompt diagnosis of the offending organism is important for accurate and effective treatment protocols to be initiated. Although technology has improved, we are still faced with challenges relating to the diagnosis of PJI.

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Diagnostic Imaging

Imaging plays a critical role in the diagnosis and management of patients with musculoskeletal infections and PJI. It is important to keep the clinical question of concern in mind, as well as the advantages and disadvantages of each imaging modality, when requesting imaging of suspected areas of infection. In many cases, imaging aids in the early diagnosis of infection, which is critical in limiting morbidity and infection-related complications. Multiple imaging modalities may be useful in diagnosing and evaluating musculoskeletal infection, including conventional radiography, MRI, CT, ultrasound, and nuclear medicine imaging.

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Conventional Radiography

Radiography is generally considered the initial study of choice by the American College of Radiology Appropriateness Criteria, and is almost always the first step in imaging areas of suspected infection.3 The main advantages of plain radiography are its ability to survey large areas of the body, widespread availability, and reproducibility; these features allow for initial baseline and follow-up evaluation. The primary drawback of plain radiography is its limited sensitivity and specificity for diagnosing osteomyelitis because a significant amount of bone loss (30% to 50%) is necessary to result in visible changes; radiographic findings may lag behind the clinical onset of disease by 1 to 2 weeks.4 In many cases, plain radiography is performed in conjunction with alternate imaging modalities to help establish the diagnosis, and the plain film result should not preclude additional imaging studies.3

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Magnetic Resonance Imaging

MRI has become a critical imaging modality in detecting musculoskeletal infections and determining the extent of disease. It is more sensitive than other imaging modalities for evaluating the extent of infection5 because of its superior soft-tissue contrast and high-resolution multiplanar technique. As a result, MRI is considered the modality of choice for detecting osteomyelitis and associated soft-tissue infections,6,7 and is complementary to plain radiography according to the American College of Radiology Appropriateness Criteria.3 The drawbacks of MRI are the relatively long acquisition times required to obtain images and the limited field of view, which may preclude the survey of large areas of the body in acutely ill patients. Additionally, MRI may be of limited value in the setting of PJI because of metal artifact, or in patients with contraindicated implantable devices, such as various pacemakers and cochlear implants.

MRI protocols vary in the setting of osteomyelitis, and the diagnosis can usually be achieved with the use of multiplanar T1-weighted nonfat-suppressed sequences and fluid-sensitive sequences. Fat-suppressed, fluid-sensitive sequences (short T1 inversion recovery or T2 with fat suppression) are the most sensitive and may show increased signal in the setting of marrow and/or periosteal edema, soft-tissue edema, and fluid collections. T1 images are most specific for the diagnosis of osteomyelitis,8 and demonstrate confluent marrow replacement with decreased signal intensity that is darker than skeletal muscle, often with associated cortical destruction or erosion. Intravenous gadolinium may not be necessary for the diagnosis of osteomyelitis9 with adequate T1 and T2 noncontrast images. However, contrast-enhanced sequences may be helpful in evaluating soft-tissue infections,10 specifically in the setting of drainable rim-enhancing fluid collections, areas of soft-tissue devitalization, or identification of sinus tracts. As with any imaging technique, MRI has its limitations; in some cases, its specificity for infection is diminished. Marrow signal changes on MRI can be seen in instances of noninfectious inflammatory arthropathy. Noninfected bone marrow signal abnormalities that are seen adjacent to areas of active soft-tissue infection may actually represent reactive osteitis and be confused with an active bone infection.11

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Computed Tomography

CT has a role in some cases of musculoskeletal infection, and its findings often overlap with those seen on plain radiography. The primary advantages of CT are high spatial resolution, the ability to survey a large area with a short scan time, multiplanar technique, and superior evaluation of soft-tissue architecture compared with plain radiography.12 Contrast-enhanced CT may be helpful to depict fluid collections, joint effusions, or areas of soft-tissue inflammation.

Dual-energy CT (DECT) is a relatively new imaging technique that has shown promise in musculoskeletal imaging applications. DECT acquires images at two different energies, typically 80 kVp and 140 kVp. Because various materials behave differently at each energy level, postprocessing techniques can be used to create virtual images that detect materials of differing atomic numbers and therefore demonstrate the chemical composition of certain structures. In musculoskeletal imaging, noncontrast DECT has the ability to discriminate uric acid deposits from calcium; these substances can be difficult to differentiate by plain radiography or conventional CT. This may be helpful in identifying cases of gout13,14 because an acute gouty flare can present in a similar fashion to infection. Also, when DECT is performed with IV contrast, postprocessing techniques allow for generation of iodine maps to assess the distribution of iodine atoms within the contrast medium and distinguish true enhancement from calcium, which may be a clue to the presence or absence of bone infection.

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Ultrasound

With ultrasound’s inability to penetrate bone, its utility to diagnose osteomyelitis is somewhat limited, but it can be useful in evaluating soft-tissue infections, particularly when there is concern for fluid collections or effusions amenable to percutaneous drainage. Thus, ultrasound is typically used for evaluation of infection confined to the soft tissues, as an adjunct to other imaging modalities in cases of osteomyelitis, or as a tool for image-guided intervention. Deep soft-tissue swelling on ultrasound is an early finding in osteomyelitis, followed by periosteal elevation and a thin layer of periosteal fluid that can progress to abscess formation.15 Ultrasound-guided aspiration may be useful for imaging around metal implants when there is concern for PJI, and it has been shown to have a higher sensitivity and specificity for predicting septic loosening of a hip prosthesis compared with fluoroscopic-guided aspiration.16

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Nuclear Medicine

Nuclear medicine imaging techniques, including bone scintigraphy, leukocyte-labeled white blood cells (technitium-99m or indium In 111), and (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET), can been used to diagnose infection. However, these modalities are becoming less common with the advent of widespread MRI and are typically considered only when MRI is not available or is contraindicated.3 In most cases, nuclear medicine imaging demonstrates poor spatial resolution compared with MRI, and it does not have the same diagnostic yield for infection.17

Three-phase bone scans may be helpful in the setting of suspected PJI because it is often difficult to distinguish PJI clinically from aseptic loosening. A negative three-phase bone scan effectively excludes both infection and aseptic loosening. Both loosening and infection demonstrate abnormal uptake around the prosthesis; however, the pattern of uptake is different. Loosening demonstrates focal uptake around the tip of the prosthesis and infection shows more generalized uptake. Leukocyte scanning with labeled white blood cells (WBC) can be achieved with either indium In 111 or 99mTc-labeled hexamethylpropylene amine oxime with a reported sensitivity and specificity between 80% to 90% for diagnosis of osteomyelitis.18,19 However, chronic infections, infections of the spine, and previous antibiotic therapy have been shown to reduce sensitivity; thus, tagged WBC studies are less useful in these circumstances.20 FDG-PET offers some advantages over other radionuclide methods because of more precise anatomic localization when performed in conjunction with CT, as well as quantitative analysis of the lesion being evaluated. FDG-PET has a reported sensitivity of >95% and a specificity of 75% to 99% for diagnosis of acute and subacute soft-tissue infection and bone infection.21 Additionally, because of FDG accumulation in macrophages, FDG-PET is useful for diagnosis of chronic and low-grade infection and has been shown to have a sensitivity of 100% and a specificity of 88% to 92% in these instances.

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Traditional Cultures: When and How

Improving the microbiologic diagnosis of PJI remains a challenge. New diagnostic methods, such as multiplex polymerase chain reaction (PCR) and mass spectrometry, are under development, but the utility of these highly sensitive diagnostic techniques with unknown specificity should be interpreted with caution.22 Such methods also fail to determine the antibiotic susceptibility of the identified organisms, thus making traditional microbiology the mainstay for identifying organisms causing PJI and determining antimicrobial susceptibility. Only by knowing the antibiotic susceptibility of the infecting organism can administration of appropriate antibiotic therapy be reasonably ensured. Unfortunately, rates of negative intraoperative cultures range from 10% to 30%, making management of these infections difficult.23 Attempts need to be made to optimize the yield of traditional cultures.

It has been recommended that antibiotic treatment be delayed in patients with suspected PJI until after cultures from the joint have been obtained, and it is widely accepted by orthopaedic surgeons that antibiotics be withheld until aspiration has been performed to increase the odds of identifying an organism.24 In one study, the sensitivity of microscopy in all patients dropped from 58% to 12% when patients received antibiotics before aspiration (native knees, 46% to 0%, prosthetic knees, 72% to 27%).25 It has also been suggested that antibiotics for surgical prophylaxis be given only after intraoperative sample collection, but more recent data suggest that a single dose of preoperative antibiotics does not significantly decrease the yield of culture results.26 Because of the known positive effects of preoperative antibiotic surgical prophylaxis in routine primary arthroplasty procedures, the authors recommend preoperative antibiotics be given before skin incision in the setting of suspected PJI.26

Three to six tissue samples should be obtained whenever possible and submitted for aerobic and anaerobic culture. Tissue swabs should be avoided because of their low sensitivity, specificity, and negative and positive predictive values compared with tissue sampling.24,27 In one retrospective study of 73 patients undergoing 77 revision arthroplasties, obtaining only one intraoperative culture was compared with obtaining five separate specimens. 28 Obtaining multiple cultures changed the microbiological diagnosis in 26 of 77 cases (34%) and the antibiotic treatment in 23 of 77 cases (30%). This analysis demonstrates that obtaining multiple cultures can significantly change patient care, and it suggests that one or two cultures are insufficient.28 Culture of synovial fluid inoculated into blood culture vials may be more sensitive than intraoperative swab and tissue cultures. Font-Vizcarra et al29 reported that synovial fluid cultured in blood culture vials had higher sensitivity, specificity, and positive and negative predictive values for diagnosis of PJI compared with standard tissue and swab samples. However, the usefulness of this technique was less in chronic infections than that in acute infections. In addition, evidence supports the use of sonication of prosthetic implants to improve microbiologic yield, especially in patients on prior antibiotics, but many microbiology laboratories have been slow to adopt this practice routinely.30

Cultures of sinus tracts and the surface of wounds should be avoided because they likely reflect skin colonization. Tetreault et al31 assessed the utility of culturing draining wounds or sinuses in patients with suspected PJI. Fifty-five patients with a draining wound or sinus after total joint arthroplasty (28 knees, 27 hips) who had not received antibiotics for at least 2 weeks were prospectively studied. Superficial wound cultures were compared with intra-articular cultures to determine the accuracy in isolating the infecting organism or organisms. The superficial cultures were concordant with deep cultures in only 26 of 55 cases (47.3%) and were more likely to yield multiple bacteria. In 23 cases (41.8%), the superficial cultures would have led to a change in antibiotic regimen. Given the potential to adversely affect patient care, we recommend against obtaining superficial cultures in patients with a draining wound or sinus following hip or knee arthroplasty.

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Intraoperative Frozen Section

Few laboratory tests are available that can be completed quickly enough to be of practical use to an orthopaedic surgeon during surgery. Although many laboratories still perform Gram stains on fluid obtained from patients with suspected PJI, it has been found to be of limited value with a sensitivity of only 27%.32 Peri-implant tissue sampling can be an effective diagnostic tool; the turnaround time for interpreting a single frozen section is approximately 20 minutes from the time it is received. Frozen sections have the advantage of being available relatively quickly, but the freezing process induces artifacts not seen in formalin-fixed tissue. For this reason, the frozen tissue blocks and other tissue from the same case are routinely processed in formalin for reinterpretation the next day (sometimes called permanent sections). Despite this limitation, experience suggests that frozen sections may be helpful to rule in or rule out infection at the time of revision arthroplasty.33

Critical to interpreting biopsies of peri-implant tissues is the recognition that different mechanisms of arthroplasty failure may produce different patterns of tissue reaction and/or inflammation. For example, frozen sections of tissue around an implant that has failed as a result of particle-induced osteolysis usually contain a high concentration of macrophages. The foamy quality of macrophage cytoplasm is caused by countless submicron particles that have been phagocytized. Perivascular lymphocytes are commonly found around many failed implants and are of unknown significance. Occasionally, cases show more diffusely distributed lymphocytes and plasma cells, but acute inflammation, characterized by neutrophils (polymorphonuclear leukocytes [PMNs]), is not a feature of particle-induced osteolysis.34 Implants that are grossly loose may induce the formation of a highly vascular membrane (granulation tissue); neutrophils are commonly seen within the capillaries and postcapillary venules of granulation tissue, but implant motion and/or fluid pressure alone are not thought to induce the movement of neutrophils out of blood vessels into the membrane itself. It follows that the absence of neutrophils on a frozen section of peri-implant tissue helps support the clinical impression of aseptic loosening.

Some implant membranes show marked acute inflammation in which the high concentration of neutrophils is essentially diagnostic of infection; however, biopsies that contain a low concentration of neutrophils can be more difficult to interpret. Many studies have attempted to define an optimum cut-off threshold for the tissue concentration of neutrophils to support the diagnosis of infection. A meta-analysis by the AAOS Clinical Practice Guidelines Committee24 identified eight studies of high enough quality to support either of two different diagnostic thresholds: (1) 10 neutrophils in each of five 400× high-power fields, or (2) 5 neutrophils in each of five high-power fields as a cut-off for diagnosing infection. The meta-analysis suggested that either level would be a good diagnostic test, but as expected, requiring fewer neutrophils per unit area slightly reduced specificity and increased sensitivity. Morawietz et al35 quantified neutrophils in 147 periprosthetic membranes from cases of aseptic loosening as well as infection, and correlated the morphologic results with the results of microbiologic cultures and clinical diagnoses. Using receiver-operating characteristic curves (ROCC), the authors suggested an optimum threshold of a total of 23 neutrophils in 10 high-power fields. This threshold yielded a sensitivity of 73% and a specificity of 95% using microbiologic cultures as the benchmark, and a sensitivity of 77% and a specificity of 97% using clinical impression as the reference standard for infection.

Several caveats should be kept in mind when interpreting frozen sections to diagnose infection during revision arthroplasty. First, joint capsules and peri-implant membranes of patients with an underlying inflammatory arthropathy (eg, rheumatoid arthritis) have not been carefully studied, thus morphologic criteria for diagnosing infection in those patients have not been established. Many of the studies that have attempted to establish a threshold of neutrophil concentrations for diagnosing periprosthetic infections have excluded patients known to have underlying inflammatory arthropathies. Also, inflammatory cells can be difficult to identify in cauterized tissue samples; thus surgeons are encouraged to use as little cautery as possible when submitting these samples for frozen section. Because surgeons often ream the femoral or tibial canal to obtain a sample, pathologists need to recognize that neutrophils within hematopoietic bone marrow do not necessarily reflect an infection.

Lymphocytes and plasma cells are commonly present in biopsies of patients who have been treated with antibiotics for infection, but these cells are nonspecific and are not predictive of active infection. Some specimens obtained at the second stage of a two-stage revision arthroplasty for known infection contain extensive surface necrosis, thick fibrous membranes, sheets of lymphocytes and plasma cells, and marked perivascular lymphocytes. These morphologic features can be similar to the inflammation that has been attributed to metal ions from failed metal-on-metal total hip prostheses,36 now sometimes referred to as an inflammatory pseudotumor.37 When this inflammatory reaction develops around an antibiotic-containing cement spacer, however, the inflammatory reaction is unlikely to reflect an immune reaction to metal ions. Finally, acute inflammation can accompany a recent periprosthetic fracture; thus a frozen section to rule out infection in the setting of a recent fracture could be interpreted as a false-positive.

With respect to the use of frozen sections to help diagnose periprosthetic infection, if there are morphologic differences between infections caused by virulent versus less virulent organisms, the question becomes whether threshold criteria should be site-specific.

The most common bacterial species associated with periprosthetic infections in the hip and knee is Staphylococcus aureus, and no evidence at this time suggests different morphologic thresholds should be used for those two sites. However, Propionibacterium acnes is thought to be a common pathogen associated with failed shoulder arthroplasty, and it is an example of an organism of relatively low virulence.

Grosso et al38 retrospectively reviewed laboratory test results of 45 patients who underwent revision shoulder arthroplasty. Multiple observations were used to define the four final clinical diagnoses of not infected, possibly infected, probably infected, or definitely infected. Routine laboratory tests, cultures, and frozen sections were obtained in all cases. Histology was reviewed, and four potential cut-off thresholds to diagnose infection were applied. The actual neutrophil counts were also obtained; therefore, a ROCC could be used to calculate an optimum threshold. There were no false-positive frozen section diagnoses, but the diagnostic sensitivity of all thresholds was lower than that usually reported for frozen sections from the hip and knee. The ROCC analysis indicated that 7 to 10 total neutrophils in 10 high-power fields would yield 72% sensitivity and 100% specificity. In general, these findings support the concept that infections associated with lower virulent bacteria may induce less pyogenic inflammation, and thus may be more difficult to recognize using the criteria generally applied to infections around the hip and knee.

Regarding whether the same criteria should be used at the second stage of a two-stage revision for known infection, we are aware of only one study that has specifically addressed this issue. Bori et al39 reviewed 21 cases of second stage reimplantation, seven of which were found to be culture-positive. The authors reviewed frozen section slides using several different cut-off thresholds and concluded the probability of infection is high when at least five PMNs per high-power field are found in the tissue, but it is not possible to rule out infection when the number of PMNs is less than five. In general, this supports one of the thresholds advocated by the AAOS Clinical Practice Guidelines committee.24

With regard to the frequency of discrepancies between the frozen section and additional samples submitted for permanent histology, and what represents optimum sampling for frozen sections during surgery, few studies have evaluated discrepancies between frozen and permanent sections in this context. Stroh et al40 reviewed frozen sections, permanent histology, and other tests in 76 patients who underwent staged revision knee arthroplasty for apparent infection. Of 304 frozen sections, 297 (97.7%) were concordant with permanent sections. There were seven false-negative frozen section interpretations; however, in each case, additional samples had been obtained during the surgery, so patient management was unaffected. In our experience, no studies provide quantitative data to support an optimum sampling protocol for frozen section diagnosis of periprosthetic infection. Additionally, there currently are no studies with adequate follow-up to determine the clinical consequences of an unexpected positive frozen section in a patient who has no other clinical or laboratory features of periprosthetic infection.

When using the recommended diagnostic thresholds, frozen sections of periprosthetic tissues around the hip and knee should have a sensitivity of 70% to 80%, with a specificity >90%. Frozen sections are less sensitive in detecting organisms of lower virulence, so a lower sensitivity is expected when hip and knee diagnostic thresholds are applied to periprosthetic tissues around shoulder implants. False-positive frozen section interpretations are rare (<2%), and are sometimes associated with tissue that has been distorted by thermal artifact. The clinical consequences of an unexpected positive frozen section in the absence of other clinical or laboratory features of infection are still unknown.

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Propionibacterium acnes Orthopaedic Infection

With improved awareness of its presence, P acnes is now recognized as the most common cause of shoulder infection.41P acnes is a slow-growing, fastidious gram-positive bacillus that resides in the pilosebaceous glands common in the axilla, especially in male patients.42,43 These glands produce more sebum in response to high-testosterone environments (eg, pubescent males); the glands can then become clogged, creating comedones and the dermatologic manifestations of acne vulgaris. The slow growth and absence of a suppurative host response makes P acnes very difficult to detect, and the bacterium was generally considered nonvirulent until recently.44

Clinical findings are frequently underwhelming. Erythema, purulence, and wound drainage are rarely observed and pain is the only consistent, although entirely nonspecific, clinical finding.43,45,46 No commercially available preoperative or intraoperative test reliably predicts subsequent P acnes growth in culture.47 Laboratory studies consisting of erythrocyte sedimentation rate, C-reactive protein level, and WBC count with differential are not helpful,43 and serum interleukin-6 (IL-6) is ineffective for diagnosis of P acnes.48 Because cultures are the only means of diagnosis, one might expect preoperative aspiration to be helpful; however, large effusions are uncommon with P acnes, thus making aspiration difficult. Fluid cultures obtained from routine aspiration have not been helpful diagnostically, and synovial leukocyte count is rarely positive.46,47 Frozen sections for acute inflammation do not correlate with ultimate culture growth.49

The current standard for diagnosis of P acnes is long-hold cultures of tissue obtained with arthroscopic biopsy,50 open biopsy, or at the time of revision surgery.47 The mean time to growth of this organism ranges from 7 to 13 days but can take up to 3 weeks, thus adding to the diagnostic challenge.46,51,52 Unfortunately, these longer hold times may contribute to growth of contaminants and potential false-positives.51 Without a widely available confirmatory test or clinical findings, the clinician must decide when to ignore and when to act on growth in only a small percentage of cultures, or growth that occurs after many days of incubation. We recommend holding cultures for 14 days, and taking at least five cultures to improve diagnostic accuracy.

Given the absence of preoperative or intraoperative findings, revisions for presumed mechanical loosening occasionally will have cultures that are unexpectedly positive. In this setting, the clinician must decide whether a positive culture represents a true infection. Patients with unexpectedly positive P acnes cultures during revision shoulder arthroplasty have good outcomes, with only 6% to 10% exhibiting persistent, demonstrable infection.53,54 However, more infections may be detected with further follow-up because this organism is slow growing.

Research has focused on identifying the true pathogenicity of P acnes infections. Some shoulder infections are clearly caused by P acnes, but the significance of P acnes detected in deep shoulder tissue or fluid may be ambiguous. Without a reliable confirmatory test, the choice of response may be confusing when a minority of cultures is positive. It is unclear whether the positive cultures are true pathogens or contaminants. Some clinicians have hypothesized there are pathogenic and nonpathogenic strains of P acnes.42,55,56 PCR has shown no genomic difference between P acnes found in implants known to be infected and those strains found in implants felt to be uninfected.56 In a small study by Nodzo et al,55 the hemolytic phenotype of P acnes on brucella blood agar was shown to be a potential marker of pathogenicity, and the authors suggest that hemolytic strains of P acnes be treated as true pathogens.

Molecular techniques currently at the investigational stage, such as PCR, hold the potential of providing a confirmatory test to definitively confirm or refute the presence of P acnes, in addition to providing information about particular strains and sensitivities that may be clinically relevant. However, these tools may be exquisitely sensitive, so much so that P acnes DNA may be detected when it is introduced to tissue from the wound margin during surgery or to the synovial fluid during arthrocentesis. Quantification of molecular results may assist in disentangling the signal-to-noise ratio, but this remains to be investigated.

Although significant progress has been made in the past decade regarding the recognition and diagnosis of P acnes orthopaedic infection, much information needs to be determined, such as periprocedural strategies that minimize the risk of introducing P acnes into the deep shoulder tissue during primary arthroplasty, reconstruction, or arthrodesis; molecular diagnostic techniques that assist with the interpretation of positive culture results in revision arthroplasty; and the optimum antibiotic regimen for treatment of P acnes detected in deep shoulder specimens that leads to improved outcomes in the long term.57

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Synovial Fluid Markers

Synovial WBC count analysis is an invaluable test for diagnosing PJI. It has a high sensitivity and specificity and, in some instances, it may be a superior diagnostic test to the benchmark of fluid culture. This test is included as a central component of the diagnostic criteria for PJI by the Musculoskeletal Infection Society and the International Consensus on Periprosthetic Joint Infection diagnostic criteria workgroup.24 One of the main advantages of this test is that a synovial fluid sample is relatively easy to obtain, and its analysis is conducted on standard hematologic measurement instruments available at hospitals worldwide. The results are generally obtained within an hour and can be immediately interpreted by the treating clinician to help establish or rule out the diagnosis of infection.

In recent years, thresholds have been established to aid in the diagnosis of PJI in many different clinical populations that include patients with chronic PJI, patients with acute postoperative infections, those with unicondylar arthroplasty, and patients with inflammatory arthropathies.58,59 Additionally, the literature suggests the synovial WBC count is similar in patients with and without systemic inflammatory conditions.58 However, this test has certain limitations. The synovial WBC count provides an analysis of the inflammatory status of the intra-articular environment without providing specific detail as to the cause of inflammation. In certain clinical situations, such as crystalline arthropathy-mediated inflammation, the inflammation could be confused with infection. Moreover, certain patients with PJI who are systemically immunosuppressed may have an artificially low WBC count that could be confused with an aseptic process. In addition, the diagnostic thresholds for infection can vary based on the clinical situation and thus require a certain baseline knowledge of which thresholds should be used with each clinical scenario. At this time, the synovial WBC count analysis provides an accurate, rapid, and easily accessible test to aid in the diagnosis of PJI; however, advancements in molecular testing may eventually supplant synovial WBC counts by providing a more specific etiology for the intra-articular inflammation beyond just demonstrating the presence of an inflammatory process.

Synovial fluid IL-6 is a potential marker in assisting with the diagnosis of PJI. Lenski et al60 evaluated synovial fluid IL-6 in 31 infected and 38 aseptic total joint arthroplasty patients. The authors found IL-6 to have a 90% sensitivity and a 94.7% specificity using ROCC. Randau et al61 found synovial IL-6 to have a specificity of 100% but a sensitivity of only 50% with levels above 9,000 pg/mL. The data support the potential use of IL-6 as a diagnostic marker, especially if threshold levels are met, but further research is necessary for routine use.

Another test demonstrated to have a high accuracy in diagnosing PJI is the synovial fluid α-defensin test.62 The α-defensin protein is an antimicrobial peptide that is released by neutrophils responding to pathogens; it concentrates in the synovial fluid, thus indicating the presence of infection. The α-defensin test has been demonstrated to closely match the results of the more complex Musculoskeletal Infection Society criteria for PJI, attaining a sensitivity of 97% and a specificity of 96% when combined with synovial fluid CRP levels.63 These results included patients on antibiotics and patients with systemic inflammatory diseases. The α-defensin testing has also been shown to outperform the leukocyte esterase test, achieving a higher accuracy in diagnosing PJI.64 The cost-effectiveness, rapid results, and analytic nature of the α-defensin test for PJI make it an excellent method to aid in the workup of patients with a painful arthroplasty.

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Summary

As the state of molecular and point-of-care diagnostics expands, the potential for a more rapid and accurate diagnosis of PJI will emerge. Intraoperative cultures and joint aspirations will remain imperative for the diagnosis of the offending organism, as well as determining antibiotic susceptibilities for treatment protocols. Frozen sections can be used to assist the surgeon intraoperatively in making real-time decisions about active acute inflammation, whereas various synovial fluid markers, such as α-defensin and IL-6, are emerging as excellent indicators of PJI. Future research should be focused on improving the diagnosis of hard to detect and slow-growing organisms such as P acnes and on establishing new, more sensitive and more specific criteria for diagnosing PJI. A definitive test for the diagnosis of PJI remains elusive, and the recommendations established by the AAOS and the International Consensus on Periprosthetic Joint Infection should be used to guide the clinician in everyday practice.

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References

References printed in bold type are those published within the past 5 years.

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