Accurate distinction of AL and PJI is essential for the optimal treatment of patients with painful lower limb joint replacements because the two conditions are treated differently[10]. AL usually requires only one revision arthroplasty to be successful[3, 4]. However, treatment for PJI is more complex, typically requiring two-stage surgery; the first stage includes implant removal, debridement, and antibiotic treatment, followed by a second-stage revision arthroplasty after control of the infection[3, 4]. Therefore, treatment for PJI is protracted, the medical costs are high, and the patients’ function and quality of life are significantly decreased[11]. An accurate and timely diagnosis is crucial for implementing the correct treatment strategy. However, AL and PJI can result in similar symptoms such as pain, swelling, and difficulty walking[6, 19, 25]; in addition, chronic and low-grade infections are more common than acute PJI in the clinical environment and such patients lack the typical clinical symptoms and signs of an infection[4, 6, 9]. This makes differentiating between AL and PJI challenging. Various clinical assessment methods are currently used to confirm the diagnosis, including laboratory examination, X-ray examination, CT imaging, MRI, bone scan, [67Ga]Ga-citrate imaging, radioactive-labelled leukocyte scintigraphy, [18F]FDG PET/CT imaging, joint aspiration, and microbial culture[3, 4, 7, 25]. However, routine laboratory tests and imaging examinations often provide non-specific results, and joint aspiration may not be successful[1, 3, 5, 9, 26]. Nuclear medicine imaging is considered one of the most valuable methods for the diagnosis of PJI and AL[3]. However, at present, various nuclear medicine methods such as [99mTc]Tc-MDP bone imaging, leukocyte scintigraphy, and [67Ga]Ga-citrate have shortcomings which limit their clinical application.
Preliminary data on the use of [68Ga]Ga-citrate PET/CT to identify bone infections are promising[16, 17]. Importantly, these studies have shown that [68Ga]Ga-citrate PET/CT may differentiate between bone infection and physiological bone healing after bone surgery[17], and distinguish infectious from non-infectious diseases after joint replacement[16]. [18F]FDG is one of the most widely studied positron imaging agents for the diagnosis of complications after prosthesis replacement. It has the advantages of high spatial resolution, good image quality, low radiation dose, and the potential for accurate anatomical localization[4, 10, 11]. Extensive literature has compared [18F]FDG with [68Ga]Ga-citrate for the diagnosis of bone infection-related diseases, and showed different results[13, 16, 17, 27, 28]. However, distinguishing bone infection from AL or physiological inflammation with [18F]FDG remains challenging[4, 9]. In addition, studies by Salomäki et al[17]. and Tseng et al[16]. have demonstrated that [18F]FDG is unable to distinguish between bone infection and physiological healing or non-infectious complications after bone surgery. Therefore, our study focused on the ability of [68Ga]Ga-citrate to distinguish between PJI and AL rather than performing a further assessment of [18F]FDG.
Our results showed that when using a Wilcoxon test, there was no significant difference in the SUVmax between PJI and AL (P = 0.448); in the ROC analysis, the AUC of SUVmax (when cut-off = 2.243 was used to distinguish PJI from AL) was 0.617 (P = 0.4312). These data indicated that SUVmax was unable to effectively distinguish PJI from AL, which is consistent with the conclusion of Tseng et al[16]. For T/NT (bone) and T/NT (muscle), the Wilcoxon test showed that there was a significant difference between PJI and AL (both P = 0.023); in the ROC analysis, the AUC of T/NT (bone) and T/NT (muscle) were 0.850 (cut-off = 2.844, P = 0.0052) and 0.850 (cut-off = 5.983, P = 0.0003), respectively. These data indicated that T/NT (bone) and T/NT (muscle) were able to effectively distinguish PJI from AL. In addition, we observed that T/NT (bone) has a good sensitivity, specificity, and accuracy (90.0%, 83.3%, and 87.5%, respectively); and the differential diagnostic efficacy of T/NT (muscle) was slightly lower than that of T/NT (bone), with a sensitivity, specificity, and accuracy of 60.0%, 100%, and 75.0%, respectively. Therefore, T/NT (bone) may be a better semi-quantitative index with excellent potential for differentiating between PJI and AL.
Our preliminary results also revealed that visual assessment (AC and NAC) of [68Ga]Ga-citrate PET/CT may be used to distinguish AL (Figs. 3 and 4) from PJI (Figs. 5 and 6) with high sensitivity, specificity and accuracy (90.0%, 83.3%, and 87.5%, respectively, for both), which is equivalent to the diagnostic effectiveness of T/NT (bone). However, two patients in our study exhibited artefacts on PET images after AC, which mimicked a slight uptake of the imaging agent by the prosthesis; these artefacts were effectively avoided in the NAC images. It is well-known that AC can cause increased tracer uptake artefacts around the prosthesis of patients with metal implants[29]. This may significantly impact the reliability of PET image interpretation in patients suspected of implant complications[29]. Therefore, we evaluated AC and NAC images in order to ensure that the lesions after AC were not imaging artefacts. Although the artefacts of the two patients examined by AC did not affect the final results of our study, we suggest that future [68Ga]Ga-citrate PET examinations in these patients should be combined with AC and NAC.
In our study, we observed a high uptake of imaging agents in the bone marrow cavities bilaterally of an elderly patient with PJI, which was significantly higher than that of the lesion. The patient had severe anaemia and received a blood transfusion two days before the examinations described in this study. This phenomenon can be explained by the fact that adults mainly rely on bone marrow for haematopoiesis, and bone marrow is active after blood transfusion or when it is in a state of self-anaemia; [68Ga]Ga-citrate is an iron analogue, which can be absorbed by active bone marrow and is therefore associated with abnormal uptake of imaging agent. In the patient who underwent a blood transfusion, although the visual analysis of the infection was unaffected it was unclear whether the SUVmax and T/NT values at the infected site were affected by bone marrow uptake. We therefore excluded this patient from the study cohort. In addition, a false-positive result occurred in one of our patients with AL one month following surgery, potentially due to the short postoperative time and the presence of a severe inflammatory reaction in the operative area. This suggests that [68Ga]Ga-citrate may not be suitable for patients who have undergone surgery recently. Similar to [67Ga]Ga-citrate, [68Ga]Ga-citrate is an inflammatory imaging agent which accumulates in the presence of both aseptic and infectious inflammation[10]. Possible mechanisms of [68Ga]Ga-citrate accumulation in such lesions includes: binding to transferrin, binding to ferritin in bacteria and lactoferrin in neutrophils, direct absorption by siderophores with a high affinity for Gallium-68, and enhanced capillary permeability at the lesion site[17, 26, 30]. AL is described as a loss of fixation of the implant that can occur as a result of inadequate initial fixation and mechanical loss of fixation over time[31, 32]. In addition, particles of wear debris may lead to macrophage activation, which in turn releases bone-resorbing products[32, 33]. This results in bone osteolysis around the implant, resulting in the biologic loss of fixation[23, 32]. Therefore, AL may be accompanied by an inflammatory immune reaction to the prosthetic material, which makes it possible for the imaging of patients with AL to show the uptake of [68Ga]Ga-citrate to a certain extent. However, the inflammatory reaction associated with AL may be significantly lower than that of infectious inflammation. In addition, neutrophils are common in PJI, but the proportion of AL cases associated with nonspecific inflammation is small (< 10%)[34]. The difference in cell composition and inflammatory reaction between AL and PJI may explain the difference in [68Ga]Ga-citrate uptake, but the overlap of cytology and histology may also explain the diagnostic difficulties encountered in this study. However, the sample size of this study was limited, and it was not possible to define the specific time period for which postoperative inflammation had a significant impact on [68Ga]Ga-citrate uptake.
With regards to the use of other imaging agents such as [18F]NaF and [18F]FDG for the diagnosis of PJI or AL, some previous studies[11, 12, 35–38] evaluated the relationship between the uptake site and final diagnosis. However, we did not evaluate this in our study. As our study involved a comprehensive assessment of complications after hip and knee arthroplasty, we employed unified diagnostic criteria to diagnose postoperative complications in two different locations. In addition, we were limited by the current sample size.
There were some limitations to our study. First, it was a single-centre study and the sample size was limited. In the current study, it was impossible to evaluate the specific period of time during which postoperative inflammation affects the uptake of the imaging agent, and it was not possible to assess the relationship between uptake sites and final diagnosis; these important issues need to be addressed in future research. Secondly, there are a few current research studies involving [68Ga]Ga-citrate, and our image analysis standards (including visual analysis and semi-quantitative analysis) were formulated comprehensively based on experience from relevant studies of [18F]NaF and [18F]FDG, combined with the small amount of existing studies of [68Ga]Ga-citrate. Given that different evaluation criteria may be associated with different results, a unified evaluation standard is needed in future studies.