Patient factors

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  Age: patients under the age of 60 years have 2 × the risk of infection compared to patients over 80 years old.

  
  
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  Male sex: males have a 1.8 × greater risk of infection compared to females.

  
  
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  Diabetes: patients with diabetes have a 1.4 × greater risk of infection compared to non-diabetics.

  
  
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  Hypoalbuminaemia: Bohl et al. showed that patients with a preoperative albumin level of less than 3.5 g/dl had a significantly higher risk of PJI in primary TKR, and hypoalbuminaemia has also been shown to decrease the success in single and two-stage revision for PJI.

  
  
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  Body mass index (BMI): patients with a BMI > 30 kg/m ² have a 1.5 × greater risk of infection compared to patients with a BMI <25 kg/m ² .

  
  
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  Inflammatory arthropathy: patients with inflammatory arthritis have a 1.4 × greater risk of infection.

  
  
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  Post-traumatic osteoarthritis (OA): patients with previous surgery for trauma have a 1.9 × greater risk of infection.

  
  
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  Intra-articular injections before TKA: Bedard et al. observed that intra-articular knee injections with corticosteroids, hyaluronic acid or other drugs prior to TKA were related to an increased risk of PJI, and this association appeared to be time-dependent: the shorter the delay between injection and TKA, the greater the likelihood of PJI.

  
  
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  Previous septic arthritis: patients with previous septic arthritis have a 4.9 × greater risk of infection.

  
  
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  Other medical co-morbidities: patients with a higher American Society of Anaesthesiologists (ASA) Grade 3 to 5 have a 1.8 × higher risk of PJI compared to those with an ASA Grade of 1. Studies have also shown that congestive heart failure, chronic pulmonary illness, preoperative anaemia, depression, renal illness, pulmonary circulation disorders, psychosis, metastatic tumour, peripheral vascular illness and valvular illness all are independent risk factors in PJI.

  
  
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  Current tobacco use: Singh et al. found that smoking was related to an elevated risk of PJI after primary TKA.

Surgical factors

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  Requirement for tibial bone graft: patients with significant tibial bone loss have a 2 × greater risk of infection.

  
  
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  Use of constrained TKR: patients requiring a posteriorly-stabilized fixed-bearing prostheses versus an unconstrained fixed bearing prosthesis have a 1.4 × increased risk of infection, and those needing a constrained condylar prostheses have 3.5 × higher risk of revision for prosthetic joint infection.

  
  
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  Prolonged operative time: patients with a postoperative infection have a mean operative time of 127 minutes, compared to 94 min in a control group.

  
  
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  Unilateral versus bilateral TKR: bilateral TKA has a significantly higher complication profile compared to unilateral TKRs.

Postoperative factors

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  Early return to theatre: patients requiring early return to theatre, including evacuation of haematoma within 30 days of index TKA, have a 12% risk of subsequent PJI.

  
  
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  Postoperative blood transfusions: patients requiring a post-operative transfusion have a 1.2 × higher risk of PJI.

  
  
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  Length of stay in hospital (LOS) over 15 days: patients with an increased LOS have an increased risk of PJI. The risk increases for increasing length, from 15 days to 24 days (HR 1.2), 25–34 days (HR 1.4) and over 35 days (HR 1.5).

  
  
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  Higher postoperative glucose variability: diabetic patients who have higher glucose level variability have an increased risk of PJI.

  
  
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  Discharge to convalescent care: patients discharged from hospital to convalescence care have a 1.3 × higher risk of PJI.

Serological markers

C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are widely available cheap blood tests that should be performed on all cases undergoing revision surgery. In acute infection with an inflammatory presentation, CRP and ESR are commonly raised, with the 2018 International Consensus Meeting (ICM) on PJI stating an acute PJI should have a CRP >100 mg/litre. It has been shown that the CRP level normalizes at approximately 3 weeks post-surgery, while the ESR level may be elevated for up to 1 year after an uncomplicated total hip or knee arthroplasty. In acute infections, the sensitivity of ESR is 42–94%, and its reported specificity ranges from 33 to 87% in the literature. The sensitivity of CRP is 74–94%, and its specificity varies between 20% and 100%.

In chronic infection, CRP elevation may be minimal, and it may vary with the virulence of the causative organism, with the ICM setting a criteria of 10 mg/litre for chronic PJI. Fernández-Sampedro et al. analysed a total of 498 patients, including 77 late PJIs. In these late PJIs, the sensitivity of CRP was only 62.3%, potentially leading to many false negative results. Greidanus et al. showed that using a combination threshold of CRP >13.5 mg/litre and ESR >22.5 mm/hour, if both tests were negative then the negative predictive value was 96%, but if both tests were positive, the positive predictive value was 84%. The problem remains that neither ESR or CRP are specific to infection, and they can be raised in many conditions.

Interleukin-6 (IL-6) is a cytokine that is released in the presence of bacterial infection or tissue damage. A 2010 meta-analysis showed superiority of IL-6 over CRP and ESR in diagnosing PJI, with a sensitivity of 97% and specificity of 91%. With the combined use of IL-6 and serum CRP, Elgeidi et al. reported a sensitivity of 100%, specificity of 99% and accuracy of 98%. However, the main problem remains the expense and lack of availability of the test.

D-dimer is a product of fibrin-clot dissolution by plasmin, and this is a commonly performed test. The increased fibrinolytic activity associated with infections results in increased D-dimer levels. Mixed results have been reported in the literature in comparison to ESR and CRP, with added problems that D-dimer is raised in the normal postoperative course, and with other conditions such as thromboembolism.

Pro-calcitonin (PCT) has recently attracted research interest in PJI, primarily due to its utility in identifying bacterial infections. PCT is normally produced by the thyroid gland, whereas in infectious conditions it is produced by macrophages and liver-derived monocytic cells. Again, there has been variability in the success of its use in diagnosing PJI, limiting its routine uptake by clinicians.

Radiology

X-ray are obtained in almost all cases of revision surgery, and may exhibit signs compatible with infection, including radiolucency and osteolysis, or rapid migration of a prosthesis that exceeds 2 mm within a 6–12-month period. However, these radiographic signs are more often seen in chronic infection, and Zajonz et al. found that radiographic evidence of infection was demonstrated in 61% of PJI in hip cases, but in only 29% for knees.

MRI is probably an underused investigation for PJI. MRI generates detailed images of soft tissues, and it is effective in detecting alterations in bone marrow, analysing fluid collections and in visualizing synovitis. The development of Metal Artefact Reduction Sequences (MARS) has helped to reduce metal artefact from the TKR, but does not illuminate it. Some studies have reported good results in distinguishing septic from aseptic failure, but it has only been adopted sparingly. In cases with evidence of osteomyelitis on X-ray, MRI can be useful in determining the extent of the infection and of soft tissue collections.

Nuclear medicine: a host of nuclear medicine investigations, including triple-phase bone scintigraphy, positive emission tomography (PET) and labelled white cell scans, have all been advocated in the investigation of PJI. White blood cells (WBCs) labelled with 99mTc-hexamethylene-propyleneamine oxime (HMPAO) or indium oxine, represent the gold-standard imaging technique for diagnosing PJI, with high sensitivity and specificity, and is the only imaging modality to be considered in the European Bone and Joint Infection Society criteria for diagnosing PJI. While this technique offers diagnostic utility, it is associated with complexity and high costs, and it is significantly time-consuming, meaning that it is often best reserved for challenging cases where PJI is suspected but remains unproven.

Synovial fluid analysis

Synovial cell counts: this method estimates the total number of leukocytes, along with an assessment of the polymorphonuclear neutrophil (PMN) percentage. Various cut-off settings have been used with various sensitivity and specificity values in a variety of different scenarios. The original synovial leukocyte count cut-off value of >10,000 cells/μl, proposed by the International Consensus Meeting, has been shown to have low sensitivity by multiple authors, in both acute and chronic PJIs. Cytological assessments can be affected by many host-related factors and by whether the patient has received antibiotics.

α-defensin (AD) is an antimicrobial peptide secreted by synovium neutrophils in reaction to infection, and targets the cell membrane of the infecting agent. It has been reported to exhibit a sensitivity range of 96–100% and a specificity exceeding 90%. Significantly, this biomarker’s diagnostic accuracy is not compromised by the administration of antibiotics, and it possesses the capability to identify a broad spectrum of microbial agents exhibiting a diverse range of virulence. A recent large-scale meta-analysis reported that laboratory-based synovial AD and synovial calprotectin were the two best independent preoperative diagnostic tests for diagnosing PJI. The assay is available in two configurations: a qualitative lateral flow test (LFT), which presents lower diagnostic accuracy, and a quantitative method, the enzyme-linked immunosorbent assay (ELISA).

Leucocyte esterase (LE) assay presents a swift diagnostic method for identifying potential PJI. This enzyme is characteristically released by neutrophils as a response mechanism to infectious stimuli. A positive (‘+’) reading on the LE test may suggest the existence of an acute infection, while a double-positive (‘++’) serves as a threshold indicative of a chronic infection. Despite the notable advantages of this test, including cost-effectiveness, wide availability and rapidity, the interpretation of outcomes remains susceptible to observer bias.

Calprotectin is a protein secreted by neutrophils, and stimulates leucocyte migration as part of the inflammatory response. Hantouly et al. conducted a comprehensive meta-analysis comprising 618 subjects across eight studies looking at the diagnostic accuracy of calprotectin. They found a cumulative sensitivity and specificity of 92% and 93% respectively.

Synovial CRP , and the combination of synovial CRP and serum CRP, has demonstrated superior diagnostic precision relative to the exclusive use of serum CRP alone. In a study conducted by Baker et al., an analysis was undertaken of 621 patients being evaluated for a revision arthroplasty due to potential PJI. Both serum and synovial CRP levels were examined, and the combination of the two resulted in an enhancement in diagnostic accuracy. They reported sensitivity as 74.6% and specificity of 98%, which were superior to serum CRP alone.

D-lactate is a metabolic by-product derived from bacterial activity, typically present within infected tissues. It has been recommended as a screening test by Karbysheva et al., who tested 224 patients with suspected PJI synovial fluid and found that it had a 92.4% sensitivity and 88.6% specificity. However, as d -lactate mirrors bacterial activity, lower levels are seen in low-virulence infections.

Microbiology culture

Aspiration and culture of the synovial fluid remains the most important investigation in infected TKR, with identification of the causative organism playing a crucial role in subsequent management. However, there are significant false negative rates due to the lower virulence of organisms in chronic infection, where there are slow replication rates. Schäfer et al. reported on 284 patients with suspected PJI who underwent cultures with a 14-day incubation period, concurrently compared with histological analysis. Findings from the study indicated an overall detection rate of 73% via culture method alone. It was observed that less virulent organisms, including Propionibacterium acnes and coagulase-negative staphylococci, were identifiable within the 14-day timeframe, but more virulent organisms such as Staph. aureus were identified typically within 7 days of culture, highlighting the need for extended cultures. The sensitivity of culture is also significantly reduced by the administration of pre-operative antibiotics. Malekzadeh et al. found that the odds of having a culture-negative specimen increase 4.7-fold if the patient had received antibiotics within the 3 months prior to aspiration or surgery. The routine practice is therefore to withhold antibiotics for at least 2 weeks prior to sampling if clinically safe to do so.

The synovial fluid and tissue also contain planktonic (free floating) bacteria, whereas the implants are covered with a biofilm containing sessile bacteria, which can be more difficult to culture. Various techniques including sonification of the implants to disrupt the biofilm can improve culture rates, but may increase contamination rates, and require careful handling.

Histology

Histological examination is very important in confirming PJI, either from tissue biopsy or from tissue taken at the time of revision surgery. Inagaki et al. conducted a comprehensive histological and microbiological analysis of 60 PJI specimens and 78 specimens from aseptic implant failures, utilizing a well-established guideline for PJI detection. Their findings indicated that a combined approach of histological and microbiological analyses yielded an accuracy rate of 98.6%. Furthermore, this approach was effective in accurately identifying aseptic failures.

In culture-negative results, there is increasing interest in molecular techniques such as next-generation sequencing (NGS). Goswami et al. conducted a multi-centre analysis on 85 patients with culture-negative PJIs, implementing to ascertain the presence of organism genetic material. Results revealed that bacteria were identifiable in 65.9% of patients with culture-negative PJIs using NGS; however, the significance of organisms identified is unsure, and the test remains expensive to perform.

Scoring systems

Due to the plethora of investigations possible and the variable sensitivity of each one, recently a multitude of scoring systems have been developed to help the guide clinician on the likelihood of infection in each situation. These systems include those developed by institutions such as the Musculoskeletal Infection Society (MSIS), the Infectious Diseases Society of America (IDSA), the International Consensus Meeting (ICM), and the European Bone and Joint Infection Society (EBJIS).