Filip Gemmel

Promising Role of 18-F-Fluoro-D-Deoxyglucose Positron Emission Tomography in Clinical Infectious Diseases

Abstract.18-F-fluoro-D-deoxyglucose positron emission tomography (FDG PET) has become an established imaging tool in clinical oncology, cardiology and neurology and is now entering the field of clinical infectious diseases. The purpose of this article is to review the currently available, albeit limited, literature on FDG PET in the diagnosis of various infections and fever of unknown origin. Those indications for which FDG PET offers added value over more available techniques like labelled leucocyte scanning, gallium scanning and magnetic resonance imaging are especially highlighted. FDG PET seems to have an incremental value in the assessment of chronic osteomyelitis, especially in the axial skeleton, as well as in the diagnostic workup of fever of unknown origin and HIV complications. Cost-effectiveness studies are needed to define its place in the current diagnostic strategies of these pathologies.

Prosthetic joint infections: radionuclide state-of-the-art imaging

Prosthetic joint replacement surgery is performed with increasing frequency. Overall the incidence of prosthetic joint infection (PJI) and subsequently prosthesis revision failure is estimated to be between 1 and 3%. Differentiating infection from aseptic mechanical loosening, which is the most common cause of prosthetic failure, is especially important because of different types of therapeutic management. Despite a thorough patient history, physical examination, multiple diagnostic tests and complex algorithms, differentiating PJI from aseptic loosening remains challenging. Among imaging modalities, radiographs are neither sensitive nor specific and cross-sectional imaging techniques, such as computed tomography and magnetic resonance imaging, are limited by hardware-induced artefacts. Radionuclide imaging reflects functional rather than anatomical changes and is not hampered by the presence of a metallic joint prosthesis. As a result scintigraphy is currently the modality of choice in the investigation of suspected PJI. Unfortunately, there is no true consensus about the gold standard technique since there are several drawbacks and limitations inherent to each modality. Bone scintigraphy (BS) is sensitive for identifying the failed joint replacement, but cannot differentiate between infection and aseptic loosening. Combined bone/gallium scintigraphy (BS/GS) offers modest improvement over BS alone for diagnosing PJI. However, due to a number of drawbacks, BS/GS has generally been superseded by other techniques but it still may have a role in neutropenic patients. Radiolabelled leucocyte scintigraphy remains the gold standard technique for diagnosing neutrophil-mediated processes. It seems to be that combined in vitro labelled leucocyte/bone marrow scintigraphy (LS/BMS), with an accuracy of about 90%, is currently the imaging modality of choice for diagnosing PJI. There are, however, significant limitations using in vitro labelled leucocytes and considerable effort has been devoted to developing alternative radiotracers, such as radiolabelled HIGs, liposomes, antigranulocyte antibodies and fragments, as well as more investigational tracers such as radiolabelled antibiotics, antimicrobial peptides, bacteriophages and thymidine kinase. On the other hand, positron emission tomography (PET) is still growing in the field of PJI imaging with radiotracers such as 18F-fluorodeoxyglucose (FDG), 18F-FDG white blood cells and 18F-fluoride. But unfortunately this superb tomographic technique will only receive full acceptance when specific PET uptake patterns can be successfully developed. The emergence of hybrid modality imaging using integrated single photon emission computed tomography (SPECT) and PET with computed tomography (SPECT/CT and PET/CT) may also have a contributing role for more accurate assessment of joint replacement complications, especially combined with new radiotracers such as 68Ga and 64Cu. Finally, in searching for infection-specific tracers, currently there is no such diagnostic agent available.

F-18 FDG PET/CT in the diagnosis of fever of unknown origin.

Methods: The utility of Fluorine-18 fluorodeoxyglucose positron emission tomography/CT in identifying the causal source was assessed in this retrospective study. A total of 68 patients (33 men, 35 women; age range, 23–91 years) with fever of unknown origin (FUO) underwent a positron emission tomography/computed tomography (PET/CT) scan. PET/CT was considered helpful when abnormal results allowed an accurate diagnosis, based on histopathology, microbiologic assays, or clinical and imaging follow-up. Results: PET/CT demonstrated suspected pathologic foci of Fluorine-18 fluorodeoxyglucose (F-18 FDG) uptake in 41 patients (60%), in 38 of these 41 patients (93%) F-18 FDG PET/CT helped in identifying the causal source, including infection in 25 patients, inflammation in 11 patients, a benign neoplasm in 1 patient, and in 1 patient rejection of a pancreas transplant. In 27 negative F-18 FDG PET/CT studies, no focal pathologic disease was diagnosed in the follow-up. In 6 of these 27 patients, a systemic disease without a focal manifestation was the cause for FUO. In the remaining 21 patients, fever and other signs subsided during follow-up. Conclusion: Overall 56% of the F-18 FDG PET/CT studies contributed in the identification of the source in patients with FUO, and elevated erythrocyte sedimentation rate and C-reactive protein (positive predictive value 93%). When systemic diseases are excluded F18-FDG PET/CT has a high negative predictive value for focal etiologies of FUO (negative predictive value 100%).

Radionuclide imaging of spinal infections

BackgroundThe diagnosis of spinal infection, with or without implants, has been a challenge for physicians for many years. Spinal infections are now being recognised more frequently, owing to aging of the population and the increasing use of spinal-fusion surgery.Discussion The diagnosis in many cases is delayed, and this may result in permanent neurological damage or even death. Laboratory evidence of infection is variable. Conventional radiography and radionuclide bone imaging lack both sensitivity and specificity. Neither in vitro labelled leucocyte scintigraphy nor 99mTc-anti-granulocyte antibody scintigraphy is especially useful, because of the frequency with which spinal infection presents as a non-specific photopenic area on these tests. Sequential bone/gallium imaging and 67Ga-SPECT are currently the radionuclide procedures of choice for spinal osteomyelitis, but these tests lack specificity, suffer from poor spatial resolution and require several days to complete. [18F]Fluoro-2-deoxy-D-glucose (FDG) PET is a promising technique for diagnosing spinal infection, and has several potential advantages over conventional radionuclide tests.Results The study is sensitive and is completed in a single session, and image quality is superior to that obtained with single-photon emitting tracers. The specificity of FDG-PET may also be superior to that of conventional tracers because degenerative bone disease and fractures usually do not produce intense FDG uptake; moreover, spinal implants do not affect FDG imaging. However, FDG-PET images have to be read with caution in patients with instrumented spinal-fusion surgery since non-specific accumulation of FDG around the fusion material is not uncommon.Conclusion In the future, PET-CT will likely provide more precise localisation of abnormalities. FDG-PET may prove to be useful for monitoring response to treatment in patients with spinal osteomyelitis. Other tracers for diagnosing spinal osteomyelitis are also under investigation, including radiolabelled antibiotics, such as 99mTc-ciprofloxacin, and radiolabelled streptavidin-biotin complex. Antimicrobial peptides display preferential binding to microorganisms over human cells and perhaps new radiopharmaceuticals will be recruited from the array of human antimicrobial peptides/proteins. In experiments with Tc-ubiquicidin-derived peptides, radioactivity at the site of infection correlated well with the number of viable bacteria present. Finally, radiolabelled antifungal tracers could potentially distinguish fungal from bacterial infections.

18-Fluorine fluorodeoxyglucose positron emission tomography for the diagnosis of infection in the postoperative spine.

Background. Using conventional imaging methods, including magnetic resonance imaging and labeled leukocyte scanning, the diagnosis of infection in the postoperative spine remains a diagnostic challenge. Recently, promising results have been reported using 18F-fluorodeoxyglucose positron emission tomography for various infectious problems. This study aimed to investigate the value of 18F-fluorodeoxyglucose positron emission tomography in patients suspected of having spinal infection after previous surgery of the spine. Methods. Fifty-seven consecutive patients with a history of previous spinal surgery were prospectively included between February 1999 and June 2001. 18F-fluorodeoxyglucose positron emission tomography was performed 60 to 90 minutes after injection of 370 MBq 18F-fluorodeoxyglucose. Images were scored visually and semiquantitatively by two blinded, independent, certified nuclear medicine physicians, experienced with positron emission tomography. Differences were assessed by consensus. Results were correlated with final diagnosis allowing calculation of sensitivity, specificity and accuracy. Receiver operating characteristic analysis was performed to find optimal cut-off values. Results. Fifteen patients had spinal infection. Using the most sensitive cut-off values sensitivity, specificity and accuracy were 100%, 81%, and 86%, respectively, for both visual and semiquantitative scoring. In the group without metallic implants (n = 27), false positives (n = 2) only occurred in the first 6 months after surgery. In the group with metallic implants (n = 30), false positives (n = 6) were not confined to recently operated patients. Conclusions. Overall accuracy was excellent (86%) with a negative predictive value of 100%. 18F-fluorodeoxyglucose positron emission tomography holds promise to become the standard imaging technique in this difficult patient population, as it is straightforward, provides a rapid result (2 hours) and because accurate alternatives are lacking.

Future Diagnostic Agents

Timely and specific diagnosis of infectious diseases can be clinically challenging but essential for the patients outcome. Laboratory tests, such as a blood culture or urine specimen, can detect the responsible micro-organism but cannot discriminate between sterile inflammatory disease and truly infectious disease. Imaging tests, like scintigraphic techniques, can pinpoint the infection in the body. There are a number of clinical scintigraphic tests from which to choose, and no single test is optimal for the various presentations of clinical infectious disease. The currently available radiopharmaceuticals often are not capable of distinguishing between sterile inflammation, and bacterial or fungal infections. Neutrophil-mediated processes, characteristic for both inflammatory and infectious processes, can be targeted in situ by radiolabeled leukocytes, antibodies or fragments, or even by cytokines and (18)F-fluorodeoxyglucose. Unfortunately those techniques are not infection-specific markers, and ongoing research is in progress to tackle this problem. The most promising option in this respect is directly targeting bacteria or fungi with radiolabeled antibiotics or antimicrobial peptides. These theoretically highly infection-specific radiopharmaceuticals could be used for monitoring the success of antimicrobial therapy of infectious disease. Although results from preclinical experiments and pilot studies in patients are promising, radiolabeled anti-infective agents are not currently in routine clinical use and studies are continuing to prove their effectiveness for diagnostic imaging of infections in the future.

Expanding role of 18F-fluoro-d-deoxyglucose PET and PET/CT in spinal infections

Abstract18F-fluoro-d-deoxyglucose positron emission tomography ([18F]-FDG PET) is successfully employed as a molecular imaging technique in oncology, and has become a promising imaging modality in the field of infection. The non-invasive diagnosis of spinal infections (SI) has been a challenge for physicians for many years. Morphological imaging modalities such as conventional radiography, computed tomography (CT), and magnetic resonance imaging (MRI) are techniques frequently used in patients with SI. However, these methods are sometimes non-specific, and difficulties in differentiating infectious from degenerative end-plate abnormalities or postoperative changes can occur. Moreover, in contrast to CT and MRI, FDG uptake in PET is not hampered by metallic implant-associated artifacts. Conventional radionuclide imaging tests, such as bone scintigraphy, labeled leukocyte, and gallium scanning, suffer from relatively poor spatial resolution and lack sensitivity, specificity, or both. Initial data show that [18F]-FDG PET is an emerging imaging technique for diagnosing SI. [18F]-FDG PET appears to be especially helpful in those cases in which MRI cannot be performed or is non-diagnostic, and as an adjunct in patients in whom the diagnosis is inconclusive. The article reviews the currently available literature on [18F]-FDG PET and PET/CT in the diagnosis of SI.

99mTc ciprofloxacin imaging for the diagnosis of infection in the postoperative spine.

BackgroundThe non-invasive assessment of postoperative spinal infections can pose a substantial diagnostic challenge, especially in the presence of orthopaedic devices. In contrast to white blood cell scanning, which is of limited use in the spine, the low uptake of 99mTc ciprofloxacin into normal bone marrow, combined with its claimed bacterial specificity, makes it, theoretically, an ideal candidate for evaluating postoperative spinal infections. AimThis study aimed to evaluate 99mTc ciprofloxacin planar and single photon emission tomography (SPET) imaging in relation to microbiological diagnosis in the postoperative spine. MethodsOnly patients with a microbiologically confirmed diagnosis were included in this analysis. Planar imaging was performed at 1, 3 and 24 h, and SPET was performed at 3 h post-injection of 370 MBq 99mTc ciprofloxacin. Images were scored by two independent, certified, nuclear medicine physicians, blinded for the final diagnosis. ResultsWithin the first 22 consecutive patients with microbiological diagnosis, there were nine deep infections. Sensitivity, specificity and accuracy at visual scoring were, respectively, 67%, 77%, 73% (1 h), 78%, 69%, 73% (3 h), and 56%, 92%, 77% (24 h) for planar imaging, and 100%, 54%, and 73% for SPET. ConclusionIn contrast to white blood cell scanning, SPET with 99mTc ciprofloxacin is sensitive in evaluating infections in the postoperative spine. Sensitivity is higher for SPET than for planar imaging. However, the results presented prove that its specificity is limited, especially in patients who have recently (<6 months) undergone surgery. Taken this limitation into account, we advise planar and SPET imaging at 3 h post-injection and at an interval of at least 6 months after surgery to minimize the chance for false positives.

Clinical trial of specific imaging of infections.

ObjectiveFor several decades 67Ga citrate, technetium-99m (99mTc) or 111In-labelled leukocytes have been used for imaging the inflammatory process. Unfortunately, these radiopharmaceuticals are not infection-specific markers. In preclinical settings, radiolabelled antimicrobial peptides (AMPs), such as UBI 29-41 seem to be highly infection-specific and even high doses of these peptides have shown neither toxicity nor side effects in animals. MethodsIn this study we present data of a recent clinical trial carried out with the 99mTc labelled antimicrobial peptide UBI 29-41 (99mTc-UBI 29-41) regarding its sensitivity, specificity, and accuracy in detecting various types of infections in 148 patients. The outcome of the trial with 99mTc-UBI 29-41 is compared with that of five other trials. ResultsPreparation of 99mTc-UBI 29-41 as a kit formulation is an easy, rapid, and reproducible process, and the tracer is very well tolerated by patients. The radiopharmaceutical has proven to be very stable and after injection into patients the biodistribution (renal clearance) and dosimetry seem to be favourable over other infection imaging radiopharmaceuticals. In this preliminary human study, patients with fever of unknown origin, osteomyelitis, diabetic foot, prosthesis infection, septic arthritis, or bacteraemia were successfully imaged with 99mTc-UBI 29-41 scintigraphy. Conclusion99mTc-UBI 29-41 is a promising agent for the specific detection of infections in humans because of its high sensitivity (96.3%), specificity (94.1%), and accuracy (95.3%) with high positive predictive (95.1%) and negative predictive values (95.5%).

Subcutaneous metastasis from an occult esophageal cancer detected by PET-CT.

We describe a unique case of an occult esophageal cancer patient without any significant symptomatology, which initially presented with a subcutaneous metastasis in the thigh. Eventually, FDG PET-CT unmasked the primary tumor of unknown origin.