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July 25, 2005

A Closer Look — PET/CT Localizes Hard-to-Find Infections
By J. K. Bucsko
Radiology Today
Vol. 6 No. 15 P. 12

It’s old news that a mounting number of Americans are not merely overweight, but obese or nearly so. Anyone involved in healthcare further understands that obesity is a primary cause of type 2 diabetes. What’s less widely appreciated, except among those who work directly with patients with diabetes, is the seriousness of such complications as nerve damage (neuropathies) and peripheral blood flow disturbances, which can further result in infections and inflammations of which patients frequently aren’t aware. The infections too often lead to gangrene and necrosis.

According to statistics compiled by the National Diabetes Information Clearinghouse, some 16 million Americans are diagnosed with diabetes. An estimated 5.4 million people are diabetic and don’t know it, with roughly 2,200 new cases diagnosed daily. Between 60% and 70% of all diabetics have at least mild nerve damage, often leading to undetected inflammation. Worse, more than 60% of nontraumatic lower-limb amputations are performed on patients with diabetes. In 2004, that represented 86,000 foot and leg amputations among the diabetic population.

Nuclear Medicine’s Role
Although best recognized for its role in oncology, PET has recently been shown to have a role in helping trace and evaluate inflammation or infection. Now pioneering research demonstrates the effectiveness of using hybrid imaging technology for pinpointing areas of bone infection among patients with diabetes.

Hybrid or fusion imaging, which involves pairing such advanced imaging techniques as PET and CT to create a combined single image, has quickly gained a high reputation among oncologists and cardiologists. New research shows how fusion imaging may provide a single-step, noninvasive diagnostic methodology for many more disease processes.

The study “The Diabetic Foot: Initial Experience with 18F-FDG PET/CT” appeared in the March issue of The Journal of Nuclear Medicine (JNM). The study’s lead author, Zohar Keidar, MD, PhD, discussed his research and where it may lead in the near future. Keidar, a member of the Virginia-based Society of Nuclear Medicine, which publishes JNM, is deputy director of the department of nuclear medicine at the Rambam Medical Center and associate senior lecturer for the Faculty of Medicine at Technion-Israel Institute of Technology, both in Haifa, Israel.

Study Objective
Because diabetes damages blood vessels, people with diabetes are at particular risk for infection in their extremities. Neuropathy is a frequent complication, so they may have advanced foot infections without being aware of it. The infections may be further complicated by osteomyelitis (bone infection) that occurs when bacteria infest bone tissue. The condition can be either acute or chronic and afflicts roughly 15% of all patients with diabetes. It further complicates up to one-third of all other diabetic foot infections. When chronic, the infection may linger sporadically for many years, resisting treatment attempts. Worst of all, the infection can be spread to other parts of the body through systemic blood circulation.

Nuclear medicine already holds a crucial position in evaluating infection. Typically, injected radiopharmaceuticals collect around damaged or diseased cells, enabling physicians to rule in or out suspected conditions. PET’s high sensitivity at the cellular level is particularly valuable in helping identify and assess diseased sites, but by itself this technology is often unable to define the anatomic location where the radiotracer is accumulating. That means the PET exam usually must be followed by additional anatomical imaging procedures, such as CT, to localize the focus of radiotracer activity and help guide a biopsy to verify the diagnosis.

Improving the State of the Art
Normally when a patient presents with the established symptoms of foot infection—including nonhealing wounds, fever, ulceration, pain, cellulitis, edema, or swelling—the physician first orders a regular x-ray series to initially verify bone infection. Frequently physicians follow this with an MRI to diagnose and localize osteomyelitis and any associated soft-tissue abnormalities.

“MRI plays an important role in the diagnosis of diabetic foot infection because of its high sensitivity and is considered by many as the modality of choice,” acknowledges Keidar. “MRI is used regularly to identify lesions, abscesses, and ulcers typically associated with osteomyelitis. Unfortunately, MRI findings of acute osteomyelitis can be confused with a number of other issues, including acutely evolving neuropathic osteoarthropathy, biomechanical stress changes related to altered weigh bearing, and bone marrow signal changes after orthopedic surgery and trauma.”

Conventional radiography and plain CT, while widely available, also come up short. Although bone structure changes will show up in both x-rays and CT, it can take up to two weeks for those changes to manifest; that interim obviously limits both systems’ value in early diagnosis. In addition, many patients with diabetes also have osteoarthritis, and distinguishing the ostemyelitis process from neuropathic changes due to the arthritic condition can be difficult. Previous studies have shown that standalone CT is sometimes unable to distinguish between infection and various other tissue conditions.

Study Results
For all these reasons, says Keidar, “we decided to investigate the role of fusion imaging in assessing infection because PET imaging using labeled glucose [18F-FDG (FDG)] can demonstrate the presence of infection, while CT shows the localization of the infection site, and at the same time detects structural changes in bone and soft tissues.”

Keidar’s team of nuclear medicine, orthopedics, and radiology physicians looked at 14 diabetic patients (primarily Type 2) presenting with 18 sites of suspected bone infection. Each underwent bone scintigraphy using 99mTechnium within one week prior to the PET/CT study. Although PET by itself identified 14 sites in 10 patients, it was unable to precisely localize the findings to soft tissue or bone.

PET/CT, on the other hand, yielded 93% specificity, confirming the diagnosis in 13 of the 14 suggestive foci and correctly localizing eight foci to bone in four patients. One site identified by plain PET as infection was localized and defined by the fused imaging technique as diabetic osteoarthropathy. PET/CT also excluded osteomyelitis in five sites in five patients by localizing abnormal FDG uptake only to the soft tissue.

Test Technology
PET/CT grafts together the two scanning technologies (PET and CT) and acquiring the separate images with the patient in the same position. Keidar’s team used a Discovery LS from GE Healthcare, which combines a third-generation, 4-slice multidetector spiral CT scanner with a dedicated full-ring PET scanner using bismuth germanate crystals. With the Discovery LS, the two scanners are mechanically aligned, back-to-back, on a shared table. Because this set-up ensures proper positioning for both acquisition modalities, it helps ensure proper registration when the two images are fused.

“CT component acquisition time was about 15 seconds and the PET part was about 10 minutes,” says Keidar. The researchers then used CT scan data to correct for low-noise attenuation of the PET emission data. Using GE’s Xeleris software, they were able to iteratively reconstruct the attenuation-corrected PET images for reviewing in axial, coronal, and sagittal planes. The system also allowed them to display the PET data as either noncorrected or attenuation-corrected images and in a rotating projection.

One drawback, as in many CT applications, was the sheer amount of data obtained in each scan. Still, Keidar says, “although there were many images generated, the ability to coregister the PET and CT data of each patient makes the localization of the findings—and hence the diagnosis—easier.”

Radionuclide Concerns
“PET and PET/CT are performed with the same isotopes,” explains Keidar. “FDG is a nonspecific tracer of increased intracellular glucose metabolism. In our study, we used the knowledge that FDG accumulates in sites of infection and inflammation. It has the advantage of a relatively long half-life, about two hours, that makes it more available for routine clinical use.” The researchers drew on a large database of studies establishing FDG’s successful use in cancer and vascular research. They were also encouraged to try FDG with PET/CT in the assessment of bone infection by recent animal studies showing that this commonly used radiotracer accumulates specifically in the site of infection, rather than in the areas of bone healing.

The high glucose levels sometimes found in patients with diabetes may affect how they metabolized the FDG, resulting in a high number of false negatives; however, as Keidar points out, “the effect of hyperglycemia on FDG uptake by inflammatory and infectious processes in diabetic patients is not well documented.” In the end, although roughly one-half of the patients presented with elevated glucose serum values at the time of testing, the researchers found no relationship between a subject’s glycemic state and FDG uptake. The result suggests that, at least in this initial study, FDG provides an effective and relatively easily obtainable means for tracing infection/inflammation and separating it from other ongoing biologic processes.

On the Horizon
Diagnosing and treating osteomyelitis in its earliest stages remains difficult because current noninvasive methodologies such as conventional radiography and even regular PET and SPECT are still unable to generate anatomically accurate images of the affected region. Now, says Keidar, “this combined imaging approach in a single session, using a single device, leads to better localization of the infection process, and thus facilitates the diagnosis.” He sees hybrid imaging as potentially having an enormous impact in the field of infection/inflammation diagnosis and treatment because it allows the physician to include or exclude specific areas of questionable tissue where activity is imaged.

“Although currently PET and PET/CT are not considered as screening tests for diagnosing asymptomatic, otherwise healthy, patients, these modalities have the advantage of showing early metabolic changes,” Keidar says. “This study shows how, using FDG, we can now localize bone involvement adjacent to soft tissue infection. Thus PET/CT has the potential to become a single-step, noninvasive technique for diagnosing infection. Based on the initial results, hybrid PET/CT … is likely to be a better, more accurate, and certainly simpler procedure for diagnosing osteomyelitis.”

Keidar anticipates that eventually “faster and more sensitive CT may lead to more accurate anatomical imaging, and, when combined with functional imaging like PET or SPECT, may eliminate the need for additional investigations with other imaging modalities.”
He speculates, “PET/CT may potentially be used to evaluate many other conditions related to infection and inflammation, such as prolonged fever, infected vascular grafts, limb prostheses, diabetic neuropathy, and related conditions.”

— J. K. Bucsko is a freelance healthcare and technology writer based in Westville, N.J. She is a frequent contributor to Radiology Today.

For More Information
Society of Nuclear Medicine
www.snm.org

National Institute of Diabetes and Digestive and Kidney Diseases of the Institutes of Health National Diabetes Information Clearinghouse
www.diabetes.niddk.nih.gov

Centers for Disease Control and Prevention Diabetes Public Health Resource
www.cdc.gov/diabetes

Related Clinical Reading
Bilohlavek O, et al. The detection of aortic valve infection by FDG-PET/CT in a patient with infection following total knee replacement. Eur J Nucl Med Mol Imaging. 2005;32(4):518.

De Winter F, Vogelaers D, Gemmel F, et al. Promising role of 18-F-fluoro-D-deoxyglucose positron emission tomography in clinical infectious diseases. Eur J Clin Microbiol Infect Dis. 2002;21(4):247-257.

Keidar Z, Engel A, Nitecki S, et al. PET/CT using 2-deoxy-2-[18F]fluoro-D-glucose for the evaluation of suspected infected vascular graft. Mol Imaging Biol. 2003;5(1):23-25.

Keidar Z, Militianu D, Melamed E, et al. The diabetic foot: Initial experience with 18F-FDG PET/CT. J Nucl Med. 2005;46(3):444-449.

Koort J, Makinen TJ, Knuuti J, et al. Comparative 18F-FDG PET of experimental Staphylococcus aureus osteomyelitis and normal bone healing. J Nucl Med. 2004;45(8):1406-1411.

Rennen HJ, Boerman OC, Oyen WJ, et al. Imaging infection/inflammation in the new millennium. Eur J Nucl Med. 2001;28(2):241-252.

Schiesser M, Stumpe KD, Trentz O, et al. Detection of metallic implant-associated infections with FDG PET in patients with trauma: Correlation with microbiologic results. Radiology. 2003;226(2):391-398.

Sella EJ, Groser DM. Imaging modalities of the diabetic foot. Clin Podiatr Med Surg. 2003;20(4):729-740.

Stadler P, Bilohlavek O, Spacek M, et al. Diagnosis of vascular prosthesis infection with FDG-PET/CT. J Vasc Surg. 2004;40(6):1246-1247.

Zhuang HM, Cortes-Blanco A, Pourdehnad M, et al. Do high glucose levels have differential effect on FDG uptake in inflammatory and malignant disorders? Nucl Med Commun. 2001;22(10):1123-1128.

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