Fracture-related infection (FRI) is one of the most prevalent and challenging complications followed by trauma surgery, especially in patients receiving orthopedic implants (1–4). The most common microorganisms causing implant-associated infections are Staphylococcus aureus and Coagulase-negative staphylococci (5). Infection is among the main causes of persistent non-union fractures and thus osteosynthesis failure, which requires invasive treatment and is a major burden for healthcare systems (6). What is more, the growing amount of placed fracture-related implants and patients with inducing conditions (e.g., diabetes mellitus and peripheral vascular diseases) may increase the incidence of FRI (7, 8).

The timely identification of infection after orthopedic surgery is essential for effective treatment (9). A consensus on how to diagnose FRI was made by the AO Foundation and European Bone and Joint Infection Society (EBJIS) recently (10), which compromised a set of confirmatory criteria (infection definitely present: for instance, fistula, sinus, purulent drainage, and the presence of pus) and suggestive criteria (infection possibly present: for instance, related clinical manifestations and radiological imaging). The evaluation of suspected FRI can be characterized by a multimodality workup containing physical and imaging examination and laboratory parameters (i.e., an elevated erythrocyte sedimentation rate and C-reactive protein). However, FRI does not always announce itself with evident symptoms. Therefore, a definite diagnosis of FRI could sometimes be quite challenging (11).

Conventional imaging methods such as plain X-rays and computed tomography (CT) can help little for the diagnosis of FRI due to nonspecific imaging features (12). Magnetic resonance imaging (MRI) can distinguish osteomyelitis with high certainty (13). However, the diagnostic value of MRI is weakened for FRI because sterile inflammation and reparative fibrovascular scar tissue usually show similar signal intensities such as reactive marrow edema (14–16). Furthermore, MRI images can be hampered by the presence of internal fixation material (17). Considering its pathophysiological processes, multiple nuclear imaging modalities such as three-phase bone scintigraphy (BS), leukocyte scintigraphy (namely, white blood cell [WBC] scintigraphy), and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/computed tomography (CT) have been investigated to evaluate the diagnostic efficacy of orthopedic surgery related infections including periprosthetic joint infection and FRI (18).

In a previously published meta-analysis, ¹⁸F-FDG PET/CT scans have presented satisfactory accuracy for the diagnosis of osteomyelitis compared with bone scintigraphy and leucocyte scintigraphy (19). Institutions using ¹⁸F-FDG PET/CT to evaluate suspected FRI are steadily growing worldwide, and this nuclear medicine imaging modality showed encouraging diagnostic accuracy based on qualitative assessments (20–24). Uptake of ¹⁸F-FDG reflects cellular glucose metabolism and can be semiquantitatively expressed as SUV, MV, TLG, etc. Increased glucose consumption induces increased ¹⁸F-FDG-uptake in the areas with enhanced metabolic activity of the tissue involved or the invasion of inflammatory cells (25–27). In addition, studies also evaluated the value of semiquantitative measurements in ¹⁸F-FDG PET/CT for the diagnosis of suspected infections for non-union fractures, and they achieved satisfactory diagnostic accuracy (28, 29). Results from previous studies indicated that ¹⁸F-FDG PET/CT could play an essential role in the diagnosis of FRI.

In clinical practice, increased uptake of ¹⁸F-FDG in inguinal lymph nodes can be frequently found during PET/CT scans in patients with suspected FRI in lower extremities. Enlargement of draining lymph nodes (DLNs) is related to infection, sterile inflammation, autoimmune disorder, cancer, and other diseases where the immune system is involved. The immune response in the DLNs can be etiology and pathogenesis specific (30–34). Thus, we supposed that the ¹⁸F-FDG uptake pattern in the inguinal DLNs could be different in fracture-related infections and aseptic inflammation in the lower extremities. To the best of our knowledge, the diagnostics value of DLNs in ¹⁸F-FDG PET/CT images for FRI has not been reported. The aim of our study, therefore, was to further evaluate semiquantitative measurements of ¹⁸F-FDG PET/CT for the diagnosis of suspected FRI with internal fixation in lower extremities and to focus not only on the suspected infection area but also the DLNs in the inguinal region.

Results of the current study showed that ¹⁸F- FDG PET/CT could be a promising diagnostic tool for FRI with internal orthopedic implants. Among all the parameters evaluated, SUVmax of the inguinal DLNs showed the best diagnostic accuracy with an AUC of 0.939, sensitivity of 86.8%, and specificity of 93.0%. To the best of our knowledge, the current study is the first one in the literature that investigated the diagnostic value of inguinal DLNs in ¹⁸F- FDG PET/CT images for FRI in lower extremities.

During the immune response, immune cell activation, infiltration, and proliferation are the basic pathological changes in the DLNs. This process can be etiology and pathogenesis specific, and therefore the immune response in inguinal DLNs, due to chronic infection or sterile inflammation, resulting from fracture-related orthopedic surgery could be different. It is well known that immune cells increase glucose analogue ¹⁸F-FDG uptake during activation, infiltration, and proliferation because of high energy consumption. So, it is reasonable to believe that the pathognomonic pattern of ¹⁸F-FDG uptake in FRI could be different from aseptic chronic inflammation not only in suspected infection regions but also in corresponding draining lymph nodes. In this study, we found SUVmax values from suspected infection areas in the lower extremities in the infected group were significantly higher than that in the non-infected group. In addition, values of metabolic parameters, including SUVmax, TLG60%, TLG70%, and TLG80% derived from inguinal DLNs in the infected group, were all significantly higher than those in the non-infected group. Interestingly, the diagnostic efficiency of SUVmax from the inguinal DLN was better than SUVmax from the suspected infection areas in the lower extremities (0.939 vs 0.836, P=0.0006).

Vera Wenter et al. (35) investigated the diagnostic value of ¹⁸F-FDG PET/CT for the detection of chronic osteomyelitis and implant-associated infection and reached a sensitivity of 70% and a specificity of 66% at the cut-off SUVmax value of 3.7. Furthermore, they found that the presence of an orthopedic implant did not reduce the diagnostic yield in patients undergoing PET/CT. Van Vliet et al. (29) used SUVmax to differentiate between aseptic and septic delayed union in the lower extremities. They found a sensitivity, specificity, and diagnostic accuracy of 65%, 77%, and 70%, respectively, at the cut-off SUVmax value of 4.0. Martina Sollini et al. (36) retrospectively tested the diagnostic performances of ¹⁸F- FDG PET/CT in non-union fractures in 47 patients. The best diagnostic performance was observed when setting the cut-off SUVmax value to 5.92 with an AUC of 0.72. The cut-off SUVmax value identified in their study was higher than in our cohort. Besides differences in patient cohorts and heterogeneous patient populations, the fact that they used microbiological culture results for specimens collected during surgery as the only reference standard to define the final diagnosis could be a significant cause for a higher cut-off value. In real-world clinical practice, the proportion of patients who could not get positive bacterial culture results were not small relatively speaking, as low virulence bacteria such as the coagulasenegative Staphylococcus species may cause culture-negative infection (37). More recently, Lemans et al. (22) reported in a large cohort of patients that the sensitivity and specificity were 80% and 72% at a cut-off SUVmax value of 4.2 for the diagnosis of FRI by using ¹⁸F-FDG PET/CT. The cut-off value of SUVmax identified in their cohort was very similar to ours. Although ¹⁸F-FDG PET/CT scans are shown to be promising in the diagnosis of FRI, the fact remains that ¹⁸F-FDG is a non-specific tracer for infection. Therefore, specific radiopharmaceutical probes targeting microorganisms are warranted in the future.

There are several limitations in this study. Firstly, it is a retrospective study, so there is a potential risk of selection bias. Retrospective studies analyze existing data and cannot control the data collection process, which may result in less accurate and reliable research findings. Secondly, some non-infected patients may not have had sufficient follow-up time, which could lead to false-negative results. Thirdly, some patients may have received antibiotics prior to PET imaging, which could affect the uptake of ¹⁸F-FDG. Lastly, the number of non-infected patients is significantly smaller than the infected group, leading to data imbalance. This imbalance could result in statistical bias, affecting the reliability of the research results. Future research can improve the reliability of results by increasing the sample size, employing stricter research designs, and controlling for relevant factors.

In conclusion, our study suggests that semiquantitative analysis (especially SUVmax) of the inguinal draining-lymph node in ¹⁸F-FDG PET/CT images shows promise as a diagnostic method for detecting FRI with internal fixation after orthopedic surgery in lower extremities. However, further research is necessary to validate and confirm these findings.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

This retrospective study was approved by the ethical review board of the Shanghai Sixth People’s Hospital.

Research conceived and designed, CS. Data acquisition, YW and ZS. Data analysis interpretation, all authors. Drafted the manuscript, XL, CS, and YW. Revised the manuscript, all authors. Obtained the funding, CS. All authors contributed to the article and approved the submitted version.