The role of three-phase 99 mTc-MDP bone scintigraphy in the diagnosis of periprosthetic joint infection of the hip and knee

Background/Aim. In the last five decades primary hip and knee arthroplasty is the most common and effective surgical intervention worldwide. Infection, although unfrequented, is the most serious complication. Nuclear medicine imaging, not affected by metallic hardware, is the current imaging modality of choice for the evaluation of suspected joint replacement infection. The aim of this study was to estimate the diagnostic accuracy of three phase 99m technetium methylene diphosphonate (99mTc-MDP) bone scintigraphy in periprosthetic hip and knee joint infection. Methods. Inclusion criteria of patients in the study were suspected knee or hip periprosthetic joint infections. In this study, we examined 45 patients (14 men and 31 women) with 39 hip and 24 knee prosthesis (total 63). In all patients, three-phase bone scintigraphy was performed after intravenous application of 555 MBq of 99mTc-MDP. The final confirmation of infection was microbiological or pathohistology finding. Results. Infection was confirmed in 29 prosthetic joints, in 13 (44.8%) knee and 16 (55.2%) hip joints while there was no infection in 34 prosthetic joints. The connection of different modalities of negative and positive findings 99mTc-MDP three-phase bone scintigraphy with the final confirmation of infection showed a high statistical significance (p < 0.001). Three phase bone scintigraphy showed a high sensitivity of 90% but a modest specificity of 69.7% in the detection of periprosthetic infection with the diagnostic accuracy of 79%. The calculated positive predictive value was 73% but the negative predictive value was high 89%. Our results of three-phase bone scintigraphy with calculated sensitivity, specificity and diagnostic accuracy of 79% are in consent with the majority of published studies, or even slightly better. Conclusion. Bone scintigraphy is sensitive in the diagnosis of periprosthetic infection but insufficiently specific. In the detection of periprosthetic infections three-phase bone scan can be used as a diagnostic method of the first line only aimed at its exclusion. The only reasonable use of bone scintigraphy is in combination with other radionuclide methods with high specificity.

three-phase bone scintigraphy with the final confirmation of infection showed a high statistical significance (p < 0.001).Three phase bone scintigraphy showed a high sensitivity of 90% but a modest specificity of 69.7% in the detection of periprosthetic infection with the diagnostic accuracy of 79%.The calculated positive predictive value was 73% but the negative predictive value was high 89%.Our results of three-phase bone scintigraphy with calculated sensitivity, specificity and diagnostic accuracy of 79% are in consent with the majority of published studies, or even slightly better.Conclusion.Bone scintigraphy is sensitive in the diagnosis of periprosthetic infection but insufficiently specific.In the detection of periprosthetic infections three-phase bone scan can be used as a diagnostic method of the first line only aimed at its exclusion.The only reasonable use of bone scintigraphy is in combination with other radionuclide methods with high specificity.

Introduction
Over the last five decades primary hip and knee arthroplasty procedures have been among the most common and effective surgical intervention worldwide 1 .The number of performed joint replacements has significantly increased in response to demographic change.The number of total hip arthroplasties (THA) carried out in the USA increased 2.5 times from 200,216 in 1993 to 497,419 in 2005.In the same period, the amount of primary total knee arthroplasties (TKA) grew 1.7-fold 2 .The most implanted artificial joints are hip and knee prostheses (more than 95%).Patients who failed conservative and comprehensive care may be considered for joint replacement surgery.Intractable pain, severe osteoarthritis (OA), and limitation of motion are the main reasons to consider joint replacement surgery.Inability to flex the knee more than 90 degrees considerably limits the functional capacity of rising from a chair.Life expectancy is also an important consideration regarding the longevity of joint replacements and the risk of future loosening or implant failure.However, some patients have prosthesis more than 20 years.The most important contraindications are an acute infection and severe obesity, while relative contraindications include: poor health and high anesthetic risks, poor bone stock, significant deformities, severe neuropathy.Although hip or knee joint replacement is highly successful surgical intervention, long-term outcomes continue to suffer from aseptic loosening and periprosthetic joint infection (PJI).More than 25% of all prostheses will demonstrate evidence of loosening, often after a revision arthroplasty 3 .Most authors agree that many cases understood as aseptic failure may be due to an unrecognized infection.
Infection, although unfrequented, is the most serious complication.In patients with primary joint replacement, the infection rate in the first 2 years usually ranges from 0.5 to 2%.Commonly isolated microorganisms are Gram-positive cocci: coagulase-negative staphylococci, Staphilococcus aureus, and enterococci (65%) 4 .Infection rates after a surgical revision are usually higher (25% to 40%) than after a primary replacement 5 .Important risk factors for arthroplasty are a postoperative surgical site infection, previous arthroplasty, older age, malnutrition, joint disease, obesity, diabetes mellitus, remote infection 6,7 .
Increased erythrocyte sedimentation rate (ESR) and high C-reactive protein (CRP) levels are sensitive for non-specific inflammation but not specific for PJI.Findings such as radiolucency, osteolysis, and migration obtained by plain radiography are not enough sensitive or specific and may be present in both infection and aseptic loosening 8 .Crosssectional imaging techniques, such as computed tomography and magnetic resonance imaging, are of limited value in the presence of metallic prosthetic implants owing to beam hardening and dephasing artefacts 9 .
Nuclear medicine imaging, which is, in general, not affected by metallic hardware, is the current imaging modality of choice for the evaluation of suspected joint replacement infection 10 .One of the oldest radionuclide imaging modalities used for this purpose is bone scintigraphy (BS) 11 .BS is widely available, relatively inexpensive, easily performed, and quickly completed.Uptake of bone-seeking tracer such as 99m technetium methylene diphosphonate ( 99m Tc-MDP), which accumulates on the surface of the bone mineral matrix, depends on blood flow and especially on the rate of new bone formation 12 .The cause of accelerated new bone formation may be seen as increased periprosthetic activity on BS in infection, but also in the postoperative physiological bone remodeling, as well as pathological conditions such as fracture, heterotopic ossification and aseptic loosening.Persistent uptake more than 12 months after arthroplasty is usually abnormal.In general, BS is highly sensitive but not very specific for PJI.The literature on the diagnostic efficiency of bone scintigraphy shows a considerable variability due to several factors, such as the use of different scan interpretation criteria (quantitative vs qualitative approach) and performing a three-phase study instead of only a delayed bone scan.
The aim of this study was to estimate the diagnostic accuracy of three phase 99m Tc-MDP bone scintigraphy in periprosthetic hip and knee joint infection.

Methods
A total of 45 patients (14 men and 31 women) with 39 implanted hip and 24 knee prosthesis (total 63) were included in this study.The mean age of patients was 68.6 (range 43-82) years.The study was performed during a 5-months period from August 2015 to January 2016.Criteria for including patients in this study were suspected PJI based on: painful prosthetic joint (especially in locomotion but also in peace), restricted joint movements and increased value of erythrocyte sedimentation rate and/or high levels of Creactive protein.All patients underwent plain radiography.In all patients, after intravenous injection of 555 MBq 99m Tc-MDP, three-phase bone scintigraphy was performed on ADAC vertex gamma camera using a large field of view dual detectors filtered with low energy all-purpose collimator.Imaging was performed at various times in supine position: 0-5 minute (15 frames in the first minute and 6 frames in further 4 minutes), 6-10 minute (one frame with 300 seconds duration) and late static imaging after 3 hours.Scintigrams were analyzed visually without any quantification.
The bone scintigraphy findings were semiquantitative: value 1 -normal, 2 -borderline normal, 3 -borderline abnormal, and 4 -clearly abnormal.The final diagnosis of infection was confirmed by microbiological or histopathological results.
For the purpose of an initial analysis and description, usual descriptive statistics were used (mean age, standard deviation, number and percentage of frequency characteristics within a given set).To test the statistical significance of differences the results of bone scintigraphy were compared with the gold standard.The χ 2 test was used and statistically significant differences were evaluated at a level of at least p < 0.05.
A software package SPSS version 18.0 (USA) was used.Sensitivity, specificity and predictive values of bone scintigraphy were calculated using the standard formulas.

Results
Descriptive parameters of patients are shown in Table 1.The relationship between the results of three-phase 99m Tc-MDP bone scintigraphy and confirmed infection is shown in Table 2.
The association between different modalities of negative and positive findings of 99m Tc-MDP three phase bone scintigraphy crossed with the final confirmation of infection showed high statistical significance (p < 0.001).
Three phase bone scintigraphy had a high sensitivity of 90% but a modest specificity of 69.7% in detecting periprosthetic joint infection, with a diagnostic accuracy of 79%.Calculated positive predictive value (PPV) was 73%, but the negative predictive value was high -89%.
Clearly positive findings of 99m Tc-MDP three-phase bo-ne scintigraphy in detecting periprosthetic joint infection of the knee are shown in Figure 1.
The high negative predictive value of 89% resulted in a frequent number of true negative findings (Figure 2).
Modest specificity of 69.7% in detecting periprosthetic joint infection resulted in false positive findings (Figure 3).

Discussion
Assessment of the presence of periprosthetic joint infection using bone scan is considered problematic by many authors.Persistently increased binding of radiopharmaceuticals in the first year after application of arthroplasty, suggesting accelerated bone remodeling, occurs in approximately 60% of cases around the femoral component of the prosthesis and in about 90% around the tibial component [13][14][15] .
Most authors agree that the accuracy of bone scintigraphy in the evaluation of possible causes of painful prosthesis varies between 50 and 70% and that it is too low value for its clinical use unless combined with some other radionuclide imaging method of higher specificity 16 .
However, according to the recent study of Zajonz et al. 2 , which included 320 prosthetic hip and knee joints, the obtained accuracy of three-phase bone scintigraphy was as much as 90%.Probably the greatest advantage of using this method alone is its high negative predictive value of 95%, making it a screening method with a high probability of periprosthetic joint infection of the hip and knee 17 .In that case should not be forgotten that the negative predictive value is lower in the first year after arthroplasty and that two-thirds of infections occur precisely in that period 8 .
Early efforts made by some authors in differentiating aseptic loosening from periprosthetic joint infection by analyzing the increased uptake were very interesting.Williamson et al. 18 found in 1979 that the focal zone of increased radiopharmaceutical uptake indicated aseptic loosening, while diffused increased radiopharmaceutical binding around the femoral or acetabular endoprosthesis indicated infection.Two years later, Williams et al. 19 reported that diffusely increased radiopharmaceutical binding around the implant might be an indication of infection and aseptic loosening.Aliabadi et al. 20 published in 1989 that bone scan could accurately detect loosening, but not separate aseptic loosening from the loosening caused by the presence of infections.Palestro et al. 21have long argued that bone scintigraphy is neither enough sensitive nor specific method in the diagnosis of a periprosthetic knee infection.This statement was supported by some recent studies, except when it comes to its sensitivity.The accuracy of this method is slightly increased if carried out as a three-phase scintigraphy.In 2008 Love et al. 16 , considering 150 prosthetic lower limb joints (96 joints of the hip and 54 joints of the knee), obtained a sensitivity of 76% and specificity of 51% in the diagnosis of infection.Diagnostic accuracy of 50% was obtained if only delayed static scintigraphy was done and increased to 62% when performed as a three-phase bone scintigraphy.
Our results of three-phase bone scintigraphy (diagnostic sensitivity 90%, specificity 69.7% and accuracy 79%) are in consent with the majority of published studies and even slightly better.

Conclusion
Bone scintigraphy is sensitive in the diagnosis of periprosthetic joint infection, but due to its unacceptable specificity, it is not a method that could work independently and can not be used alone for detecting a periprosthetic joint infection.For that purpose, the three-phase bone scan can be used as the first line diagnostic method just for the definitive exclusion of infection.The only realistic possibility to use bone scintigraphy to detect a periprosthetic joint infection is its combination with other radionuclide methods of high specificity.

Fig. 1 -Fig. 2 -
Fig. 1 -A 72-year-old female patient with bilateral knee joint replacement.In the region of right knee replacement extensive increased activity is observed in all three phase of bone scintigraphy indicating infection.

Fig. 3 -
Fig. 3 -Positive findings at all stages of the imaging (increased uptake in the region of the greater trochanter and discreetly increased along the femoral stem).Definitive result: aseptic loosening.

Table 2 The relationship between the results of 99m Tc-MDP and confirmed infection
99mTc-MDP -technetium methylene diphosphonate.