Diagnosing periprosthetic joint infections (PJI): where to start, what to look for


While a periprosthetic joint infection (PJI) is more likely to occur within the first two years of implantation, any artificial joint is at an increased risk of developing infection over its lifetime. Diagnosing PJI is not always straightforward—patients may not have obvious symptoms. Detection of infection requires a multi-disciplinary approach characterized by good communication and weighted problem-solving based on the right information. What signs of infection should a clinician be on the lookout for? What combination of testing, imaging, and cultures is recommended? Part 2 of this article series examines the complexities of PJI diagnosis.

Periprosthetic joint infection (PJI) is a growing problem [1, 2]. Even if rates of infection hold steady, the simple fact that more joints are being replaced translates into a higher number of PJI cases [3–6]. The prevalence of multi-drug resistant PJIs is also a “worrisome” trend [7]. The microorganisms that tend to colonize artificial joints grow in biofilms that present a challenging host of problems in terms of diagnosis and treatment [8–10].

The complex nature of PJIs necessitates a multidisciplinary approach to coordinate decision making. The weighted evaluation of the information gathered at each step of diagnosis and treatment requires cross-disciplinary collaboration and communication [11]. See Part 1 of this article series for further elaboration of PJI risk factors and pre-, intra-, and postoperative infection prevention strategies. Part 3 examines treatment options for acute and chronic PJI.

In addition to the increased economic cost related to PJI [12], there is an often unacknowledged personal cost for surgeons who may feel responsible. In qualitative telephone interviews with orthopedic surgeons, Mallon et al chronicled “a significant emotional impact on surgeons who report a collective sense of devastation and personal ownership, even though prosthetic joint infection cannot be fully controlled for.” [13]


Most common pathogens in PJI

A 2014 study on the most common PJI pathogens compared 898 cases from an infection referral center in Germany to 772 cases at a similar institution in the US. A higher number of virulent and resistant organisms were identified as the source of infection in the US center. The organisms that were identified were: coagulase-negative Staphylococcus, Staphylococcus aureus, Streptococcus spp, Enterococcus spp, anaerobes, fungi, and mycobacteria. Additionally, they found polymicrobial and culture-negative infections [14]. Other causative agents are gram-negative bacteria (such as Klebsiella spp, Pseudomonas aeruginosa), and Cutibacterium spp [15].

This is a long list of suspects, each with unique biomarkers, culturing requirements, antibiotic susceptibility, and antibiotic dosing specifications and delivery pathways (intravenous vs oral). However, it is worth mentioning that there are also other infection-causing microorganisms rarely associated with PJI and this uncommonness may prolong or complicate their identification—they are not routinely tested for [16–19]. Testing for rare microorganisms has been recommended, particularly in persistent cases [18, 20].


Did you miss AO Recon’s webinar on periprosthetic joint infection (PJI)?

In June 2019, AO Recon gathered an online community of close to 200 surgeons for an interactive information session and Q&A led by Olivier Borens, Head of Septic Surgery and Head of Traumatology at the Centre Hospitalier Universitaire Vaudois (Lausanne, Switzerland) and chat moderator Andrej Trampuz, Infectious Diseases Consultant in Septic Surgery at Charité–Universitätsmedizin (Berlin, Germany) on the topic of infection after joint arthroplasty.


Biofilm: the orthopedic surgeon’s nemesis

When microbes grow as a biofilm they multiply into slimy, multi-layered, sometime multi-species, complex, synergistic communities. The microorganisms (bacteria and fungi) adhere to each other as well as surfaces, such as prosthetic joints, chemically communicating with each other. Bacteria in a biofilm share available nutrients and gain protection from hostile environmental threats such as antibiotics and the body’s immune defenses through a variety of strategies [21]. It is hypothesized that biofilm formation evolved as a survival strategy during the time of primitive Earth [22].

As they mature, biofilms, such as those formed by common PJI-causing Staphylococcus spp, can develop extracellular barriers, making it difficult for the body’s immune cells to penetrate, and even deactivate those that do manage to get through [23]. And most importantly in terms of PJI, biofilms are less sensitive to antibiotics via several inherent biological mechanisms [9]. Figure 1 highlights the intensifying complexity of a biofilm through its stages of maturity—it can be more straightforward to diagnosis and treat an infection before it forms a biofilm. Figure 1 also illustrates the persistence of biofilms, which when associated with PJI make them more difficult to predict, diagnose, and treat [24].

Figure 1. Biofilm Maturation Is a Complex Developmental Process Involving Five Stages. Five stages of biofilm development: (1) initial attachment, (2) irreversible attachment, (3) maturation I, (4) maturation II, and (5) dispersion. Each stage of development in the diagram is paired with a photomicrograph of a developing Pseudomonas aeruginosa biofilm. All photomicrographs are shown to the same scale. Used with permission under CC License. From: Monroe, D. Looking for chinks in the armor of bacterial biofilms. 2007. PLoS Biology 5 (11, e307). DOI:10.1371/journal.pbio.0050307. Image credit: Davis D.

 
However, early PJI detection is not always possible and once you have a suspicion of infection there is no single test that can reliably be used to diagnose it, which means that a combination of diagnostic testing must be employed and interpreted [25–28]. 

 
Signs and symptoms

Let’s look at the symptoms that should be on both the clinician and patient’s radar. Infection can be divided into acute and chronic categories, each with distinctive infection characteristics (Table 1). In the case of acute PJI, patients may report fever, effusion, sudden onset of pain, erythema, and/or swelling and warmth at the implant site. To be classified as acute, the symptoms will have developed within the first 4 weeks of surgery: symptom duration should not have exceeded four weeks. Acute infections occur either postoperatively early after surgery—even years after the last surgery—by hematogenous spread of a distant infection. Highly virulent microorganisms are generally associated with this type of infection [8, 15, 29].

Andrej Trampuz, Infectious Diseases Consultant in Septic Surgery at Charité—Universitätsmedizin in Berlin, Germany, indicates that “pain is the most sensitive symptom of chronic (low-grade) PJI, although it is not specific. Pain due to chronic infection is typically more intense at rest and at night, typically appears in the first months to years after arthroplasty and worsens over time, and may be accompanied with periprosthetic osteolysis or heterotopic ossifications.”

Chronic (low-grade) PJI may present more subtly and with less obvious clinical symptoms, such as persistent joint pain and aseptic loosening. These symptoms also point to aseptic failure as a possible source of the discomfort and it can be challenging to identify which is going on. A sinus tract or fistula may be visible [15]. A chronic infection is associated with onset of symptoms more than 4 weeks postoperatively. Usually, less virulent microorganisms are responsible for these infections [8].

Olivier Borens, Head of Septic Surgery and Head of Traumatology at the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, notes that “The most difficult PJI to diagnose is the low-grade infection without any evident signs of infection. It’s more likely to appear as a joint arthroplasty which is slightly painful, and doesn’t feel right, without redness, fever, or fistulation. It’s like a jigsaw puzzle where you have to put discrete signs of infection together to get to a diagnosis.”

However, depending on pathogenesis, the time to onset and symptoms, and their duration, will likely differ, and also is indicative of acute or chronic infection. If PJI strikes within 1 year after surgery, the infection is likely to be caused by microbes introduced during the procedure [30]. One estimate from 2004 indicated that 2–5% of implants were contaminated before implantation [31].

 
Table 1. Classification of prosthetic joint infection

Used with permission. From: Pocket Guide to Diagnosis & Treatment of PJI; PRO-IMPLANT Foundation (October 2019).

 
Reconnaissance: know your adversary

In addition to clinical symptoms that may or may not be present, a number of additional investigations are recommended to help determine if PJI is present and what pathogen(s) are responsible. the European Society of Radiology (ESR), European Bone and Joint Infection Society (EBJIS), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) suggest starting with a clinical examination, laboratory tests, and planar x-rays. These would then be followed by joint aspiration, microbiological analysis, and advanced imaging [32].

 
Imaging

Plain x-rays are recommended as a first step for patients presenting with a painful joint [27, 33]. Borens points out that when looking for acute or chronic infection, they can be very “similar for the two as the clinical signs are very subtle. The surgeon needs to look for signs of early loosening on the x-ray, maybe infection parameters in the blood will give indication, however, these are often normal!”

The American College of Radiology (ACR) Appropriateness Criteria® Imaging After Total Knee Arthroplasty has published a document outlining 12 variants of scenarios related to knee arthroplasty, including three specifically related to infection investigations [33]. The ACR recommendations rate the appropriateness of various imaging modalities and include a column indicating radiation exposure levels for each modality.

There is no single imaging modality that will deliver a diagnosis. The clinician has a number of options to consider and the type of imaging selected will depend on symptoms, as well as how far along in the diagnosis process you have gone. Table 2 is a selection of the most commonly performed imaging types and some of the positive and negative considerations for each.

 
Table 2. Selected pros and cons of recommended periprosthetic joint infection (PJI) imaging options

 
Laboratory testing

Testing for serum biomarkers is less invasive and less costly than synovial fluid analysis [35]. In the past, routine blood tests such as white blood cell count (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), or procalcitonin (PCT) were commonly conducted [27]. These tests have been found to not offer the sensitivity or specificity needed, particularly in chronic (low-virulence) PJI; for recent implants they may only indicate post-surgical inflammation [29, 40]. ESR and CRP may also be elevated in patients with inflammatory diseases [35]. However, if a suspected PJI patient presents with a fever, blood cultures are recommended [32].

 
Synovial fluid aspiration

According to Izakovicova et al, synovial fluid leukocyte count and granulocytes percentage, collected via pre-operative joint aspiration, is the “most valuable diagnostic tool”. They recommend this be done for every painful joint before revision and suggest these indicators will help to exclude aseptic loosening as a cause of symptoms [29].

In the case of unspecific symptoms, “diagnostic joint aspiration is needed to confirm infection in patients reporting joint pain, independent of the blood inflammatory parameters such as leukocytes or C-reactive protein (CRP). The leukocyte count and percentage of granulocytes in the synovial fluid is the single most important preoperative test, together with a 14-day synovial fluid culture,” says Trampuz.

Keep in mind that up to 32% of aspiration procedures don’t acquire enough fluid for analysis [41]. Aspiration should not be done through overlying cellulitis as it risks contaminating the sample [42]. It is advised to stop antibiotic treatment for 2 weeks before obtaining a sample with this method [32].

In terms of diagnostic criteria, the PRO-IMPLANT Foundation recommends a cut-off count of > 2000/μl leukocytes or > 70% granulocytes (polymorphonuclear neutrophils (PMN)) as indication of infection (see Figure 3) [15]. C-reactive protein is generated in the liver not the joints, and while it is considered a general indicator of inflammation, non-elevated CRP levels in synovial fluid do not exclude PJI [32].

However, careful reading of these results is imperative. Trampuz notes that “interpretation of the synovial fluid leukocyte and culture results is important since false-positive and false-negative results may occur. Therefore, comprehensive definition criteria for PJI were developed, taking into account a mosaic of pre- and intraoperative tests to accurately diagnose or exclude infection [see Figure 3].”

A biomarker analysis that appears to complement existing diagnostic options is the measurement of alpha defensin in synovial fluid. Based on its high specificity (> 95%) it may be used as a confirmatory test. However, due to its low sensitivity, especially in low-grade infections, it is not a reliable screening test [43]. Another synovial fluid biomarker that is being tested for effective PJI detection is D-lactate. A 2019 study by Yermak et al reported similar efficacy as a leukocyte count but it only requires a small volume of synovial fluid, has a short analysis time (it is analyzed spectrophotometrically), and lower cost [44].

 
Microbiology

Obtaining samples for culture is the next step in the diagnostic process. Culturing these samples has the added benefit of indicating the infectious microorganism(s) present, and if a polymicrobial infection is present—multiple infectious agents in a PJI may be the reality for 10–20% of cases [4, 42]. Watanabe et al describe an enrichment culture method and found it to offer a higher detection rate of infection in PJI cases, recommending it over standard culture methods [45].

Culturing tissue samples surgically obtained from the joint in question is the most reliable way to detect pathogens [8]. Collecting at least three or more samples for culture is recommended and swab cultures should be avoided [8, 29, 46].


Golden rules for collecting PJI samples for microbiology

Here is short list of best practices related to microbiology sample collection for the diagnosis of periprosthetic joint infections and implant-related infections in orthopedics [46].

  • Do not use swabs
  • Collect appropriate microbiological samples (explanted devices, synovial fluid, and 3 to 6 periprosthetic tissue specimens)
  • Avoid sample contamination (use clean gloves and instruments; avoid contact of samples with the patient’s skin at any time)
  • Use closed and sterile transport systems for samples
  • Use sonication for explanted prosthetic components
  • Incubate cultures for 14 days, including aerobic and anaerobic conditions. In cases of culture-negative infections, look for rare and atypical microbes (eg, fungi, mycoplasma, mycobacteria)
  • Perform antimicrobial susceptibility testing for relevant antibiotics (eg, rifampicin in Staphylococci spp, ciprofloxin in gram-negative rods)
  • Polymerase chain reaction and new generation sequencing systems need to be further investigated and validated before they can be recommended as routine diagnostics
  • Use a standardized reporting policy to clinicians of the microbiologic results

Accurate synovial fluid culturing relies on the use of suitable transport medium, such as pediatric blood culture bottles [47, 48], a short transportation time to the laboratory [29], and an incubation time of at least 14 days (to find low-virulent pathogens like Cutibacterium spp) [49, 50]. Culturing synovial fluid has an added benefit of being able to detect polymicrobial or fungal infections [51].

However, if an infection is culture-negative, it will not be detected in this type of investigation. Indeed, the use of molecular diagnostic techniques to identify pathogens has indicated that up to 34% of PJI fall within this culture-negative category [50, 52].

 
Sonication

While submerged in enriched liquid, explanted prosthetic devices are subjected to low-frequency ultrasound to shake loose biofilm microorganisms. This liquid this then sent for aerobic and anaerobic culturing. Sonication has been shown to be effective in detecting chronic infections and in cases even when the patient has received recent antibiotics. It is more sensitive than the standard culture of tissue samples [53].

Handling, storage, and transport of explanted materials will impact results. After removing device components, do not place them in plastic bags. Place components into sterile, ridged, plastic containers to limit contamination [29]. Antibiotic bone-cement (PMMA) associated with spacers that are removed and sonicated in a two-stage procedure were shown to inhibit microorganism growth during culturing, particularly daptomycin and gentamicin. The antibiotics are distributed via elution and together with sonication, carry a risk of delivering a false-negative [54].

Interestingly, the heat output of sonication fluid was indicative of microbial growth and metabolism in a study conducted by Borens et al. In 10.9 hours (faster than culturing), microcalorimetric readings of the fluid indicated the presence of microorganisms [55]. This test did not give indication of what kind of pathogen was present; it is best described as a “rapid and reproducible” screening for infection.

 
Molecular methods

Polymerase chain reaction (PCR) is superior to culture in the detection of low-virulent bacteria, eg, coagulase-negative staphylococci [56]. Multiplex PCR can also deliver results within 5 hours, in an automated analysis [57]. This is in contrast to standard culture which needs days to weeks for sufficient growth [56]. One marked benefit of using PCR to analyze synovial fluid is it the fact that it retains high specificity and sensitivity in patients on antibiotics [58]. However, PCR is expensive [59] and susceptible to contamination [60, 61].

 
Tissue histology

Considered a standard procedure in diagnosing PJI [29], histopathology of periprosthetic tissue samples is used to detect markers of acute inflammation [8]. Two histological techniques are used: frozen sections for intraoperative histological assessment and paraffin sections for final or postoperative assessment [62]. Depending on the preparation of the sample, frozen or paraffin, there has been a recorded discrepancy in diagnosis for the same patient [63].

Neutrophil granulocytes are counted at high-power field magnification of 400, with Bemer et al suggesting ⩾ 23 granulocytes per 10 high-power fields as the “gold-standard” threshold [64]. However, the inflammatory cell count can widely vary between tissue samples from the same patient and is also dependent on the observer.[8] Despite these shortcomings, histology for PJI shows high sensitivity and specificity (95%, 92%, respectively) [65].


Histological determination of virulence now possible with the the CD15 focus score [29, 66]

Histological diagnosis is a multi-disciplinary process reliant on the sharing of clinical, laboratory, imaging, and biomechanical data. Pathologists catalogue morphological changes in periprosthetic tissue using a classification based on observations of the synovial-like interface membrane (SLIM) [66]. Recently added to their PJI diagnosis toolbox is the quantification of CD15 positive granulocytes, the “CD15 focus score”, as a means of stratifying low-virulence and high-virulence microbial pathogens. A count of 39 CD15 neutrophilic granulocyte (NG)/focal point was identified as the optimum threshold when diagnosing PJI. Displaying high sensitivity and specificity, the CD15 focus score could help point clinicians in the direction of specific antibiotic treatment, particularly in the event of conflicting or unclear findings.


Diagnose PJI if at least one of these criteria is satisfied

How can you be sure that PJI is a potential diagnosis for a patient’s symptoms? Over the years, different PJI definition criteria have been put forward. However, chronic (low-grade) PJI were being missed. The PRO-IMPLANT Foundation has tabulated pertinent information on the criteria that should be used to capture chronic, low-virulence pathogens with an improved sensitivity, as presented in Table 3.

Table 3. Definition of periprosthetic joint infection. It is diagnosed if ≥ 1 criterion is fulfilled

a Metal-on-metal bearing components can simulate pus (“pseudopus”), leukocyte count is usually normal (metal debris is visible)

b Leukocyte count can be high without infection in the first 6 weeks after surgery, in rheumatic joint disease (including crystalopathy), periprosthetic fracture or luxation. Leukocyte count should be determined within 24 h after aspiration by microscopy or automated counter; clotted specimens are treated with 10 µl hyaluronidase

c Classification after Krenn and Morawietz: PJI corresponds to type 2 or type 3

d For highly virulent organisms (eg, S aureus, Streptococci, E coli) or patients under antibiotics, already one positive sample confirms infection

e Under antibiotics, for S aureus and anaerobes, <50 CFU/mL can be significant

Used with permission. From: Pocket Guide to Diagnosis & Treatment of PJI; PRO-IMPLANT Foundation (October 2019).

 
What you’ve been waiting for

Wouldn’t it be helpful if there was an algorithm for diagnostic flow that captured all the elements that clinicians should consider when confronting the possibility of PJI? The PRO-IMPLANT Foundation has assembled just that—an evidence-based diagnostic algorithm that provides a guided, visual pathway through this complex decision-making process (see Figure 2).
 

Figure 2. Diagnostic algorithm for periprosthetic joint infection. Used with permission. From the Pocket Guide to Diagnosis & Treatment of PJI; PRO-IMPLANT Foundation (October 2019).

 
Conclusion

After working through the diagnostic algorithm and its associated tests, it is determined that a patient does indeed have indication of a PJI. Or perhaps testing was inconclusive and during revision further evidence of infection is gained? What are the next steps? Rest assured, there is a treatment algorithm as well as surgical intervention timing and antimicrobial therapy recommendations. Borens feels strongly that, “the more surgeons adapt to well-defined guidelines, the better the results will be and we will be able to better analyze the success rates of any given treatment protocol.” Knowing what the problem entails is the first step toward delivering an effective treatment plan.

Part 3 of this article series takes you through appropriate treatment options for several PJI scenarios. Part 1 of this article series looks at the pre-, intra-, and postoperative strategies for preventing PJI.

Contributing experts

This series of articles was created with the support of the following specialists (in alphabetical order):


Olivier Borens

University Hospital Lausanne, Switzerland

Nora Renz

Inselspital, University Hospital
Bern, Switzerland

Andrej Trampuz

Charité - University Medicine
Berlin, Germany

This issue was created by Word+Vision Media Productions, Switzerland.

Additional Resources

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