Periprosthetic joint infection (PJI) is a serious complication that can occur after joint replacement surgery, such as knee or hip replacement. This refers to an infection involving tissues surrounding the artificial joint [1,2]. This infection can occur days or years following the initial joint replacement surgery. The most common bacteria associated with periprosthetic joint infections are Staphylococcus aureus and coagulase-negative staphylococci, although other types of bacteria may also be involved. Periprosthetic joint infection (PJI) is one of the most intractable diseases in the orthopedic field, partly because of the difficulty in differentiating infectious from non-infectious conditions. Diagnostic advances have contributed to improvements in the treatment of PJI [1,3,4,5,6,7,8]. Universal diagnostic criteria were established in the 2013 and 2018 International Consensus Meeting (ICM) for PJI [6,7]. The advantage of the latest 2018 ICM criteria is that the scoring system enables PJI diagnosis with a higher accuracy than before. However, one of the disadvantages of the ICM criteria is the complexity of the multifaceted diagnostic tests, which include serum biomarkers, synovial fluid tests, operative findings, and tissue examination. Some of these tests, such as microbiological cultures, histopathological assessments, and alpha defensin tests for synovial fluids, are difficult to complete preoperatively, although the diagnosis significantly affects the treatment approaches in cases of aseptic loosening or PJI.

In patients undergoing total joint replacement surgery, there is a possibility of loosening occurring between the implanted prosthesis and the bone. In such cases, revision surgery involving the removal of the loosened implant and insertion of a new implant is necessary [8]. Implant loosening can be classified as infectious (PJI) or aseptic non-infectious loosening. In non-infectious cases, replacing the implant with a new one is typically sufficient for revision surgery. However, in PJI cases, it is essential to thoroughly cleanse the bacterial focus, debride the area, and ensure bacterial eradication. In patients with PJI, performing implant revision surgery with a bacterial focus may lead to early postoperative reinfection and recurrent implant loosening. For patients with prosthetic joint infection (PJI) presenting with extensive bone loss, significant soft tissue damage, multidrug-resistant bacterial infections, or cases in which the causative pathogen is unidentified, a two-stage revision procedure is recommended [8]. This involves removing the implant to conduct infection treatment, followed by delayed re-implantation after a specified interval. As the number of surgeries increases, the damage to the bone and soft tissue also escalates, rendering the treatment of PJI challenging. Therefore, the preoperative diagnosis of infection is crucial for appropriate treatment selection and improved postoperative outcomes in patients with infectious loosening. However, diagnosing infection before revision surgery in PJI patients poses challenges, owing to the limited availability of methods. In cases of indolent infections, particularly in patients with unidentified causative pathogens, bacteria adherent to the implant periphery often form biofilms and enter a viable but non-culturable (VBNC) state [9]. This frequently results in negative bacterial cultures, making the definitive diagnosis of infection challenging even in the postoperative period. The misdiagnosis of infectious loosening as non-infectious loosening can result in patients undergoing inappropriate repeated joint replacement surgeries. To avoid the misdiagnosis of septic and aseptic loosening, universally applicable screening tests are necessary in all facilities.

Among the ICM 2018 laboratory tests, serum biomarkers are the simplest and most sensitive diagnostic methods [6]. This test has been demonstrated to be an effective screening method for PJI and should be performed as the first step in patients when there is even the slightest suspicion of PJI [1]. The ICM 2018 criteria incorporate the C-reactive protein (CRP), the erythrocyte sedimentation rate (ESR), and the D-dimer as the test parameters, and these test methods have been reported to be suitable blood diagnostic methods [6]. In contrast, culture-negative PJI reportedly shows lower CRP levels, which often complicates the detection of low-grade PJI in clinical practice [10]. Therefore, serum screening tests that can detect physical responses to infection may improve the preoperative diagnostic accuracy of PJI. In various medical fields, serum albumin (Alb) is used as a nutritional indicator and predictive marker for cancer prognosis and infectious diseases [11,12,13].

Diagnosis before surgery is essential for the appropriate treatment of PJI, as there are significantly different treatment approaches for aseptic loosening. In the field of orthopedic infectious diseases, diagnostic imaging using computed tomography (CT) or Magnetic Resonance Imaging (MRI) is commonly employed for the identification of infectious regions in the bone and soft tissue. However, in cases of prosthetic joint infection (PJI), the presence of artifacts due to implants makes diagnostic imaging using CT and MRI challenging. Instead, nuclear medicine modalities have been reported to be useful in the diagnosis of PJI [1,27,28,29,30]. Nevertheless, nuclear medicine exams pose challenges in terms of cost and facility requirements as standard imaging diagnostics, making their use in routine preoperative screening difficult. Therefore, for the preoperative diagnosis of PJI, blood tests and joint synovial fluid analyses are essential. Furthermore, even when synovial fluid aspiration is performed before surgery, patients from whom joint fluid cannot be collected due to a dry tap necessitate screening solely through blood tests. The 2013 and 2018 ICM criteria are the globally recognized diagnostic criteria for PJI [6,7]. These multifaceted diagnostic criteria have improved the accuracy of PJI diagnosis. However, these criteria include diagnostic methods that are difficult to implement in general hospitals and some diagnostic tests that yield results only after surgery. Hence, a simple screening test that can be completed before surgery, is feasible in general hospitals, and has sufficient accuracy is in great demand for patients with PJI, especially in patients presenting with a dry tap for synovial fluid and difficulty in preoperatively achieving a definitive diagnosis.

Among various infectious diseases, preoperative serum tests are the most convenient and effective method of preoperative screening. The C-reactive protein (CRP) test is the most straightforward and convenient method for quantitatively assessing inflammation and is commonly used to evaluate the intensity of infection and inflammation in various infectious diseases. The CRP, discovered in 1930 by William Smith Tillett and Thomas Francis in the United States, undergoes precipitation reactions with the C-polysaccharide of pneumococci [31,32]. It activates the immune response against bacteria by binding to them, and its elevation of production during bacterial infections has led to its widespread use in clinical settings for the diagnosis and assessment of infections [31,32]. Its high accuracy has led to its recommendation for screening in the diagnosis of prosthetic joint infection (PJI) [1,6]. The erythrocyte sedimentation rate (ESR) test measures the rate at which red blood cells settle in a solution. The causes of an elevated ESR include a decrease in red blood cells or albumin levels and an increase in gamma globulin or fibrinogen levels.

The combination of CRP and ESR is recommended in the diagnostic flowchart for PJI proposed by the American Academy of Orthopaedic Surgeons (AAOS) as an early and simple screening method [1,33]. Indeed, the combination of CRP and ESR has been widely reported to maintain excellent accuracy in PJI diagnosis. In the 2018 International Consensus Meeting (ICM), the measurement of the D-dimer was also recommended [6]. The D-dimer, a fibrin degradation product yielded when fibrin is broken down by plasmin, has been a crucial test in blood examinations for suspected thrombotic disorders, such as venous thromboembolism, since its introduction in the 1990s [31,32]. Although the D-dimer has been reported as a useful serological diagnostic method for PJI, conflicting reports on its utility in PJI diagnosis exist [34]. Numerous reports have suggested the usefulness of other coagulation and fibrinolysis system blood test markers in PJI diagnosis [35]. In recent years, various blood markers have been applied in the diagnosis of PJI, including ratios such as the neutrophil-to-lymphocyte ratio and the platelet count, which have also been reported as useful indicators of a patient’s immune status in the diagnosis of PJI [35].

Among diverse patient populations, however, there are individuals who exhibit low levels of inflammatory markers, even in the presence of bacterial infections, due to comorbidities and concurrent treatment, or patients who exhibit high CRP levels even in the absence of bacterial infections [10,36]. Recently, a combination of various blood markers has been reported to be useful for improving the accuracy of infectious disease diagnosis compared to a single inflammation marker [35,37]. Among serum markers, Alb and Glb are widely used in the diagnosis or prediction of malignant tumors, postoperative mortality, and orthopedic infectious diseases [21,38,39,40,41,42].

Albumin is a protein predominantly synthesized in the liver and serves as a straightforward indicator of nutritional status through simple blood tests [43]. In patients undergoing orthopedic surgery, low levels of albumin are recognized as a significant risk factor that independently induces various complications [12]. Following the onset of infection, trauma, and inflammation, storage proteins in the body such as muscles and albumin undergo degradation, leading to the enhanced production of the inflammatory protein CRP (C-reactive protein) to activate the immune response [43]. Alb is widely associated with the immune system and performs various biological functions [43]. Low albumin levels suggest decreased immune response and malnutrition. Moreover, elevated levels of CRP in conjunction with low albumin levels indicate a decline in albumin production and increased breakdown due to inflammation or infection. Alb levels are negatively correlated with CRP levels owing to the biological effect of interleukin (IL)-6 on hepatocytes, which increases CRP production and reduces Alb production [44]. Glb, also known as immunoglobulin, can be quantified by subtracting Alb from the total protein in serum examinations [43], and, in patients with infectious conditions, IL-6 production also increases immunoglobulin levels. Thus, Glb levels are representative of antibody production and have been used to evaluate the overall status of immune responses to infections. As the sum of Alb and Glb is equal to the total protein level, the AGR sensitively reflects the immune activation of individuals, and this biological pathway may explain the high accuracy of Glb, AGR, CAR, and CRP/AGR tests. Interestingly, the optimal cutoff value for AGR screening was 1.1 or 1.2 in four different studies, indicating the consistency of these serum tests, although the other biomarkers showed widely variable cutoff values among the studies. The choice of cutoff values significantly affects both sensitivity and specificity; however, the optimal cutoff values for diagnostic markers can differ based on the patient background or bacterial organisms [10,24]. Therefore, the AGR can be considered a reliable diagnostic tool because it showed consistent cutoff values in many studies.

Serum Alb, Glb, and AGR measurement is a commonly used blood screening method for nutrients and inflammatory disorders in general hospitals, alongside the serum CRP measurement and combination indices of AGR, CAR, and CAGR [23]. These combination indices were demonstrated to have a high sensitivity and may possibly provide a better diagnosis without additional invasive procedures or new technology. The cumulative AUC for the AGR was favorable (0.84). Moreover, the AUC for the combination marker of CRP/AGR was 0.91, which was higher than the diagnostic accuracy of CRP alone. This suggests that the AGR can identify PJI cases with abnormal values, which may be difficult to screen using CRP alone. Indeed, two studies demonstrated the utility of the AGR in the detection of low-grade PJI, defined as PJI with <10 mg/L [21,25]. This implies that, by incorporating immunological markers, such as Alb and Glb, in addition to inflammatory markers, such as CRP, blood-based PJI screening can be performed with a higher sensitivity. Many tests offer the flexibility to set different cutoff values, allowing them to be employed as highly sensitive screening tools or as more specific diagnostic tests, depending on their biological characteristics. Thus, it may be possible to improve the preoperative diagnostic accuracy of PJI by setting two different cutoff values for each serum biomarker and assigning different scores in the current scoring system for PJI diagnosis. If the two highly specific markers were elevated to a significant degree, it would enable the preoperative diagnosis of PJI using only serum tests. This serum diagnosis could improve the accuracy of the preoperative diagnosis of PJI and facilitate a treatment approach focused on addressing infection. For this purpose, it is essential to combine two distinct serum markers with different biological characteristics to eliminate potential patient-related factors for misleading diagnoses. Alb, Glb, and AGR are effective potential candidates for the diagnosis of PJI.

In conclusion, serum Alb, Glb, and AGR levels in combination with CRP levels are feasible and accurate diagnostic markers for PJI and can improve the preoperative diagnostic accuracy of PJI.