Pitfalls and Limitations of Radionuclide and Hybrid Imaging in Infection and Inflammation.

Both the referring clinician and the nuclear medicine specialist must be aware of the main known or potential pitfalls that can occur in infection and inflammation imaging. They must decide in consensus which tracer and which imaging protocol should be used for a specific indication. This article provides an overview of all the pitfalls and limitations of nuclear medicine techniques to image infections and inflammation. Both general pitfalls and pitfalls in specific clinical entities are discussed.

Comparison of FDG and FDG-labeled leukocytes PET/CT in diagnosis of infection.

UNLABELLED: The aim of this study is to compare FDG and FDG-labeled leukocyte (WBC) PET/CT in the diagnosis of infection using different SUV and visual thresholds for interpretation. Patients, material, method: 49 consecutive patients (27 men, 22 women, mean age: 55.7 years, range: 16-89 years) with suspected musculoskeletal infection (n = 34), vascular graft infection (n = 5), aortitis (n =1 ), endocarditis (n = 1), mass lesion which is suspicious for infection or malignity (n = 6), and fever of unknown origin (n = 2) underwent both FDG and WBC-PET/CT. Images were evaluated by both visual analysis (grade 1-3) according to uptake intensity and quantitative grading (grade 1-3) based on lesion to background SUVmax values. Final diagnosis was made by histopathological, microbiological analysis or clinical-radiological work-up. RESULTS: The diagnosis of infection was made in total 24 patients, of whom 14 were diagnosed by histopathological and the rest by clinical-radiological work-up. WBC-PET/CT imaging with the visual threshold of 1b as infection positivity (for truncal lesions uptake equivalent to liver or lumbar vertebrae uptake; for extremity lesions uptake significantly higher than neighbouring soft tissue uptake or higher than neighbouring bone marrow uptake) was found to have the highest diagnostic accuracy (AUC: 0.874, CI: 0.771-0.997, p < 0.001). The optimal SUV threshold was found to be 8.8 (p = 0.006; sensitivity: 72.7%, specificity: 82.8) and 5.3 (p < 0.001; sensitivity: 81.8%, specificity: 79.3%) for FDG and WBC-PET/CT, respectively by ROC curve analysis. CONCLUSION: WBC-PET/CT is more valuable than FDG PET/CT in the imaging of infection. Visual threshold of >1b seems to be more suitable for detection of infection.

Quantification of the chromosomal radiation damage induced by labelling of leukocytes with [18F]FDG.

INTRODUCTION: The aim of our work is to quantify the radiation damage in lymphocytes after labelling with [18F]FDG. Comparison with gold standard [99mTc]HMPAO labelling is established. An approach to cellular dosimetry is proposed. METHODS: Mixed leukocytes were separated from fresh venous blood and labelled with [18F]FDG and [99mTc]HMPAO following published guidelines. Cytokinesis-block micronucleus (CBMN) assay was performed for both sets of experiments. Tests for quality control of labelling described in guidelines were followed. Cellular dosimetry was calculated according to MIRD. RESULTS: MN scored after labelling with 37 MBq of [18F]FDG were 956 ± 172 and 347 ± 26 for [99mTc]HMPAO (p < 0.05). Absorbed dose in cell nucleus was of 0.23 Gy for [18F]FDG and 0.08 Gy for [99mTc]HMPAO labelling. The CBMN assay after labelling with ~290 MBq of [18F]FDG showed radiation induced inhibition of proliferation capacity of the lymphocytes, confirmed by proliferation study. CONCLUSIONS: [18F]FDG labelling of mixed leukocytes causes severe radiation damage to the cell, higher than with [99mTc]HMPAO in accordance with the absorbed dose. Labelling of mixed leukocytes for clinical purpose induces high cytotoxicity reflected in the loss of proliferation capacity in lymphocytes this statement allows us to consider a low oncogenic risk however the association between MN formation in the PBL and subsequent risk of cancer is not well established. ADVANCES IN KNOWLEDGE: This is the first work about radiation damage with [18F]FDG labelled cells. We focused on [18F]FDG labelling of leukocytes due to the growing number of research and review articles about this technique. IMPLICATIONS FOR PATIENT CARE: The possibility of an increased risk of lymphoid malignancies associated with the administration of radiolabelled lymphocytes is a very controversial subject. Studies on radiation damage on new labelling procedures as the one exposed in this work must be considered.

Precise fusion of MRI and dual energy 111In WBC/99mTc HDP SPECT/CT in the diabetic foot using companion CT: an example of SPECT/MRI imaging.

AIM: The purpose of our study was to correctly fuse MRI and SPECT ¹¹¹In WBC and 99m Tc HDP images using companion CT images. The fused images could be used to assess proper surgical approach in treatment of the diabetic foot. METHODS: Nine patients who had dual energy ¹¹¹In WBC/ 99m Tc HDP SPECT/CT and MRI studies within a week were investigated in an ongoing project. A GE Infinia SPECT/CT camera and Siemens MAGNETOM 1.5T MR system were used in this study. First, the MRI and corresponding CT images were coregistrated using a transformation based on normalized mutual information. The transformation was saved and used for MRI and ¹¹¹In WBC/ 99m Tc HDP SPECT fusion. A Jaszczak phantom study was also performed in order to estimate accuracy of MRI/ SPECT fusion. RESULTS: The Jaszczak phantom study with 3.7 MBq ¹¹¹In hot sphere showed that MRI/SPECT alignment using the approach described above produced registration with 0.7 ± 0.4 mm accuracy in all three dimensions (3D). The nine clinical cases were visually evaluated and showed 1-2 mm 3D fusion accuracy. MRI provides almost perfect anatomy of soft tissue and bony structures but it may exaggerate the extent of infection. ¹¹¹In WBC/99m Tc HDP SPECT imaging is more accurate for infection detection but lacks anatomical reference. Combination of these images proved an essential adjunct to diagnosis. A clinical utility of the approach is illustrated in two clinical examples. CONCLUSION: The CT in dual energy ¹¹¹In WBC/99m Tc HDP SPECT/CT studies can be used to accurately fuse and compare ¹¹¹In WBC/99m Tc HDP SPECT and MRI images of the diabetic foot. This can significantly help in conservative treatment planning and limb salvage procedures in treatment of diabetic foot infections.

The use of functional imaging in the diagnosis of carotid patch infection.

Carotid patch infection following carotid patch angioplasty is a rare but serious complication. Accurate diagnosis is vital yet currently ill-defined. We present the use of computed tomography positron emission tomography and leucocyte radioisotope scintigraphy and highlight their potential role in the diagnosis of equivocal carotid patch infection.

PET/CT with 18F-FDG- and 18F-FBEM-labeled leukocytes for metabolic activity and leukocyte recruitment monitoring in a mouse model of pulmonary fibrosis.

UNLABELLED: Idiopathic pulmonary fibrosis is characterized by a progressive and irreversible respiratory failure. Validated noninvasive methods able to assess disease activity are essential for prognostic purposes as well as for the evaluation of emerging antifibrotic treatments. METHODS: C57BL/6 mice were used in a murine model of pulmonary fibrosis induced by an intratracheal instillation of bleomycin (control mice were instilled with a saline solution). At different times after instillation, PET/CT with (18)F-FDG- or (18)F-4-fluorobenzamido-N-ethylamino-maleimide ((18)F-FBEM)-labeled leukocytes was performed to assess metabolic activity and leukocyte recruitment, respectively. RESULTS: In bleomycin-treated mice, a higher metabolic activity was measured on (18)F-FDG PET/CT scans from day 7 to day 24 after instillation, with a peak of activity measured at day 14. Of note, lung mean standardized uptake values correlated with bleomycin doses, histologic score of fibrosis, lung hydroxyproline content, and weight loss. Moreover, during the inflammatory phase of the model (day 7), but not the fibrotic phase (day 23), bleomycin-treated mice presented with an enhanced leukocyte recruitment as assessed by (18)F-FBEM-labeled leukocyte PET/CT. Autoradiographic analysis of lung sections and CD45 immunostaining confirm the higher and early recruitment of leukocytes in bleomycin-treated mice, compared with control mice. CONCLUSION: (18)F-FDG- and (18)F-FBEM-labeled leukocyte PET/CT enable monitoring of metabolic activity and leukocyte recruitment in a mouse model of pulmonary fibrosis. Implications for preclinical evaluation of antifibrotic therapy are expected.

Respective performance of 18F-FDG PET and radiolabeled leukocyte scintigraphy for the diagnosis of prosthetic valve endocarditis.

UNLABELLED: Echocardiography plays a key role in the diagnosis of infective endocarditis (IE) but can be inconclusive in patients in whom prosthetic valve endocarditis (PVE) is suspected. The incremental diagnostic value of (18)F-FDG PET and radiolabeled leukocyte scintigraphy in IE patients has already been reported. The aim of this study was to compare the respective performance of (18)F-FDG PET and leukocyte scintigraphy for the diagnosis of PVE in 39 patients. METHODS: (18)F-FDG PET and leukocyte scintigraphy were performed on 39 consecutive patients admitted because of clinically suspected PVE and inconclusive echocardiography results. The results of (18)F-FDG PET and leukocyte scintigraphy were analyzed separately and retrospectively by experienced physicians masked to the results of the other imaging technique and to patient outcome. The final Duke-Li IE classification was made after a 3-mo follow-up. RESULTS: Of the 39 patients, 14 were classified as having definite IE, 4 as having possible IE, and 21 as not having IE. The average interval between (18)F-FDG PET and leukocyte scintigraphy was 7 ± 7 d. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 93%, 71%, 68%, 94%, and 80%, respectively, for (18)F-FDG PET and 64%, 100%, 100%, 81%, and 86%, respectively, for leukocyte scintigraphy. Discrepancies between the results of (18)F-FDG PET and leukocyte scintigraphy occurred in 12 patients (31%). In patients with definite IE, 5 had true-positive (18)F-FDG PET results but false-negative leukocyte scintigraphy results. Of these 5 patients, 3 had nonpyogenic microorganism IE (Coxiella or Candida). Of patients for whom endocarditis had been excluded, 6 had true-negative leukocyte scintigraphy results but false-positive (18)F-FDG PET results. These 6 patients had been imaged in the first 2 mo after the last cardiac surgery. The last patient with a discrepancy between (18)F-FDG PET and leukocyte scintigraphy was classified as having possible endocarditis and had positive (18)F-FDG PET results and negative leukocyte scintigraphy results. CONCLUSION: (18)F-FDG PET offers high sensitivity for the detection of active infection in patients with suspected PVE and inconclusive echocardiography results. Leukocyte scintigraphy offers a higher specificity, however, than (18)F-FDG PET for diagnosis of IE and should be considered in cases of inconclusive (18)F-FDG PET findings or in the first 2 mo after cardiac surgery.

PET/CT with 18F-FDG-labeled autologous leukocytes for the diagnosis of infected fluid collections in acute pancreatitis.

UNLABELLED: Early detection of infection in acute pancreatitis (AP) affects the choice of treatment and clinical outcome. We used PET/CT with (18)F-FDG-labeled autologous leukocytes to detect infection in pancreatic or peripancreatic fluid collections in patients with AP. METHODS: Forty-one patients (28 men and 13 women) who were 21-69 y old (mean ± SD, 41 ± 11.5) and had AP and radiologic evidence of a fluid collection in or around the pancreas were studied. Leukocytes were separated from the patient's venous blood, labeled with (18)F-FDG, and reinjected intravenously; PET/CT images were acquired 2 h later. A final diagnosis of infection was based on microbiologic culture of fluid aspirated from the collection. Patients were treated with supportive care and antibiotics; percutaneous drainage or laparotomy was performed when indicated. RESULTS: Blood glucose level, total leukocyte count, neutrophil count, and leukocyte labeling efficiency varied from 83 to 212 mg/100 mL (118 ± 30), 4,600 to 24,200/mm(3) (11,648 ± 5,376), 55% to 90% (73 ± 10), and 31% to 97% (81 ± 17), respectively. Increased tracer uptake in the fluid collection was seen in 12 of 41 patients; 10 had culture-proven infection and underwent percutaneous drainage, and aspiration was unsuccessful in 2. The scan results were negative for infection in 29 patients; 25 had fluid culture results that were negative for infection, and aspiration was unsuccessful in 4. The sensitivity, specificity, and accuracy of the scan were all 100% in 35 patients for whom fluid culture reports were available. CONCLUSION: PET/CT with (18)F-FDG-labeled leukocytes is a noninvasive and reliable method for the diagnosis of infection in pancreatic or peripancreatic fluid collections in patients with AP.

FDG PET for diagnosing infection in hip and knee prostheses: prospective study in 221 prostheses and subgroup comparison with combined (111)In-labeled leukocyte/(99m)Tc-sulfur colloid bone marrow imaging in 88 prostheses.

PURPOSE: This study aims to assess and compare the value of FDG PET with combined In-labeled leukocyte/Tc-sulfur colloid bone marrow (WBC/BM) imaging for diagnosing infection in hip and knee prostheses. METHODS: In this prospective study, patients with painful hip or knee arthroplasty, who were scheduled to undergo clinical and diagnostic evaluation for prosthesis revision, were included. They have been studied by using FDG PET and WBC/BM scan. This study was institutional review board approved and Health Insurance Portability and Accountability Act compliant. All patients provided written informed consent. RESULTS: A total of 134 hip and 87 knee prostheses, suspected of being either infected or noninfectious loosening, were evaluated. All 221 prostheses underwent FDG PET, whereas both WBC/BM imaging and FDG PET were performed in 88 prostheses. The initial analysis of data from the WBC/BM images demonstrated somewhat suboptimal results compared with those of FDG PET scans on 88 patients. In addition, some patients were not willing to undergo both procedures and therefore participate in this study. Therefore, a decision was made to eliminate WBC/BM imaging from the procedures for the remainder of this research study. This decision was reached partly because of the significant radiation dose delivered from labeled WBC and safety issues related to preparing these labeled cells. Final diagnosis was based on microbiological examinations of the surgical specimens in 125 prostheses and joint aspirations combined with the clinical follow-up of 6 months or more in 86 prostheses. The sensitivity, specificity, positive predictive value, and negative predictive value of FDG PET in hip prostheses were 81.8%, 93.1%, 79.4%, and 94.0%, respectively, and in knee prostheses were 94.7%, 88.2%, 69.2%, and 98.4%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of WBC/BM imaging in hip prostheses were 38.5%, 95.7%, 71.4%, and 84.6%, respectively, and in knee prostheses were 33.3%, 88.5%, 25.0%, and 92.0%, respectively. In those cases that underwent both FDG PET and WBC/BM imaging, there was a trend (P = 0.0625) toward a higher sensitivity for FDG PET in hip prostheses, whereas other comparisons did not show any significant differences between the 2 imaging modalities. CONCLUSIONS: Based on this study, the diagnostic performance of FDG PET scan in detecting infection in painful hip and knee prostheses is optimal for routine clinical application. Considering the complexity and costs of WBC/BM imaging and related safety issues associated with this preparation, FDG PET seems to be an appropriate alternative for assessing these patients.

Painful knee arthroplasty.

A triple-tracer nuclear medicine study that incorporates (99m)Tc-sulfur colloid, (111)In-labeled leukocytes, and (99m)Tc-methylene diphosphonate can be useful for the diagnosis of aseptic loosening in a patient after total-knee arthroplasty, as demonstrated in this case study. The triple-tracer technique takes less time and is more accurate than a bone scan alone.

Usefulness of adding SPECT/CT to 99mTc-hexamethylpropylene amine oxime (HMPAO)-labeled leukocyte imaging for diagnosing prosthetic joint infections.

OBJECTIVE: This study evaluated the usefulness of adding single-photon emission computed tomography (SPECT)/computed tomography (CT) (SPECT/CT) to technetium Tc 99m (Tc) hexamethylpropylene amine oxime (HMPAO)-labeled leukocyte imaging for diagnosing infections in hip or knee joint prostheses. METHODS: The Tc-HMPAO-labeled leukocyte scans of 164 patients (71 with hip prostheses and 93 with knee prostheses) with clinically suspected prosthetic infections were reviewed retrospectively. Planar images were taken 4 to 6 and 21 to 26 hours after injecting the labeled leukocytes and SPECT/CT images were obtained 4 to 6 hours after the injection. The final diagnosis of infection was based on pathologic findings (n = 70), bacteriological data (n = 61), or clinical follow-up (n = 33). RESULTS: Of the 164 patients, 89 patients had a diagnosis of prosthetic joint infections. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of the planar images alone were 82.0%, 88.0%, 89.0%, 80.5%, and 84.8%, respectively. When the planar images were combined with SPECT, the sensitivity, specificity, PPV, NPV, and diagnostic accuracy were 91.0%, 88.0%, 90.0%, 89.2%, and 89.6%, respectively. When the planar images were combined with SPECT/CT, these values increased further to 93.3%, 93.3%, 94.3%, 92.1%, and 93.3%, respectively. Adding CT to SPECT resulted in a greater increase in sensitivity and specificity for hip prosthesis infections than for knee prosthesis infections. SPECT/CT mainly contributed by precisely localizing the anatomical site of the active inflammatory lesion and by delineating the extent of the lesion after diagnosis with SPECT. CONCLUSIONS: Single-photon emission computed tomography/CT combined with Tc-HMPAO-labeled leukocyte imaging was useful for diagnosing prosthesis infections, particularly in hip prosthesis infections, as it improved diagnostic accuracy and provided anatomical localization data.

Native Aortic and Prosthetic Vascular Stent Infection on 99mTc-Labeled White Blood Cell Scintigraphy.

The value of (99m)Tc-labeled white blood cell scintigraphy for endovascular prosthetic infections is well known. In the unique case reported here, infection of the native aorta was detected in addition to an infected vascular prosthesis. The case demonstrates that (99m)Tc-labeled white blood cell scintigraphy can identify not only the more usual prosthetic stent/graft infection but also infection of the native aorta. When scrutinizing studies for infection of prosthetic material, readers should also carefully examine the native aorta.

Detection of infected liver cysts by 111In WBC SPECT/CT in polycystic liver disease.

SPECT/CT imaging can provide improved diagnostic information over traditional planar scintigraphy and SPECT, with more precise anatomic localization and observer confidence. We present 2 patients with polycystic liver disease (PCLD), both with constitutional symptoms and bacteremia. In WBC SPECT/CT images revealed increased WBC localization within a single liver cyst in each case, subsequently drained under imaging guidance. Cultures confirmed the presence of infection, allowing for appropriately directed antibiotic therapy and successful treatment outcomes. These cases illustrate the incremental value of In WBC SPECT/CT fusion imaging for the evaluation of bacteremia in complicated patients.

Image acquisition and interpretation criteria for 99mTc-HMPAO-labelled white blood cell scintigraphy: results of a multicentre study.

PURPOSE: There is no consensus yet on the best protocol for planar image acquisition and interpretation of radiolabelled white blood cell (WBC) scintigraphy. This may account for differences in reported diagnostic accuracy amongst different centres. METHODS: This was a multicentre retrospective study analysing 235 WBC scans divided into two groups. The first group of scans (105 patients) were acquired with a fixed-time acquisition protocol and the second group (130 patients) were acquired with a decay time-corrected acquisition protocol. Planar images were interpreted both qualitatively and semiquantitatively. Three blinded readers analysed the images. RESULTS: The most accurate imaging acquisition protocol comprised image acquisition at 3 - 4 h and at 20 - 24 h in time mode with acquisition times corrected for isotope decay. CONCLUSION: Using this protocol, visual analysis had high sensitivity and specificity in the diagnosis of infection. Semiquantitative analysis could be used in doubtful cases, with no cut-off for the percentage increase in radiolabelled WBC over time, as a criterion to define a positive scan.

FDG and FDG-labelled leucocyte PET/CT in the imaging of prosthetic joint infection.

PURPOSE: The demand for arthroplasty is rapidly growing as a result of the ageing of the population. Although complications such as heterotrophic ossification, fracture and dislocation are relatively rare, differentiating aseptic loosening, the most common complication of arthroplasty from infection, is a major challenge for clinicians. Radionuclide imaging is currently the imaging modality of choice since it is not affected by orthopaedic hardware. Whereas FDG PET/CT imaging has been widely used in periprosthetic infection, it cannot discriminate aseptic from septic inflammation. In this study we aimed to evaluate the role of FDG PET/CT and FDG-labelled leucocyte PET/CT in the diagnosis of periprosthetic infection. METHODS: Of 54 patients with painful joint arthroplasty who were imaged by FDG PET/CT for diagnosis of periprosthetic infection examined, 46 (36 women, 10 men; mean age 61.04 ± 12.2 years, range 32-89 years) with 54 painful joint prostheses (19 hip, 35 knee) with grade 2 (above liver uptake) FDG accumulation on FDG PET/CT were included in the study and these 46 patients also underwent FDG-labelled leucocyte PET/CT. Final diagnoses were made by histopathological-microbiological culture or clinical follow-up. RESULTS: The final diagnosis showed infection in 15 (28%) and aseptic loosening in 39 (72%) of the 54 prostheses. FDG PET/CT was found to have a positive predictive value of 28% (15/54). Since patients with no FDG uptake on FDG PET/CT were excluded from the study, the sensitivity, specificity, negative predictive value and accuracy could not be calculated. The sensitivity, specificity, and positive and negative predictive values of FDG-labelled leucocyte PET/CT were 93.3% (14/15), 97.4% (38/39), 93.3% and 97.4%, respectively. CONCLUSION: Since FDG is not specific to infection, the specificity of FDG PET/CT was very low. FDG-labelled leucocyte PET/CT with its high specificity may be a useful method and better than labelled leucocyte scintigraphy in periprosthetic infection imaging.