CONTINUING EDUCATION Imaging of Inflammation by PET, Conventional Scintigraphy, and Other Imaging Techniques Martin Gotthardt1,2, Chantal P. Bleeker-Rovers2,3, Otto C. Boerman1,2, and Wim J.G. Oyen1,2 1Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 2Nijmegen Institute for Infection, Inflammation and Immunity, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; and 3Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Learning Objectives: On successful completion of this activity, participants should be able to describe (1) the role of nuclear medicine imaging techniques in the detection of inflammatory diseases; (2) the mechanisms of uptake of radiotracers into inflamed tissue; and (3) the respective advantages and disadvantages of different imaging modalities in the detection of inflammatory diseases, including PET, SPECT, ultrasonography, MRI, and CT. Financial Disclosure: The authors of this article have indicated no relevant relationships that could be perceived as a real or apparent conflict of interest. CME Credit: SNM is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNM designates each JNM continuing education article for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should claim only credit commensurate with the extent of their participation in the activity. For CE credit, participants can access this activity through the SNM Web site (http://www.snm.org/ce_online) through December 2011. imaging procedures. The approach to diagnosing a specific Nuclear medicine imaging procedures play an important role inflammatory disease depends on the type of suspected in the assessment of inflammatory diseases. With the advent disease and the clinical presentation. Therefore, the context of 3-dimensional anatomic imaging, there has been a ten- in which imaging procedures are used varies considerably. dency to replace traditional planar scintigraphy by CT or MRI. For many inflammatory diseases, no unequivocal guidelines Furthermore, scintigraphic techniques may have to be com- bined with other imaging modalities to achieve high sensitivity for the use of imaging procedures exist, but in some cases and specificity, and some may require time-consuming label- there is sufficient evidence from the literature to advise on ing procedures. On the other hand, new developments such imaging procedures for optimal diagnosis or follow-up. In as combined SPECT/CT increase the diagnostic power of other cases, local factors and specific expertise with a cer- scintigraphy. Also, the advent of PET had a considerable im- tain diagnostic algorithm may play an important role. Here, pact on the use of nuclear medicine imaging techniques. In we provide a concise summary of the most important this review, we aim to provide nuclear medicine specialists and widespread nuclear medicine imaging techniques in and clinicians with the relevant information on rational and efficient use of nuclear medicine imaging techniques in the inflammatory diseases for clinicians and nuclear medicine assessment of patients with osteomyelitis, infected vascular specialists. This paper focuses on imaging in important prostheses, metastatic infectious disease, rheumatoid arthri- infectious diseases such as osteomyelitis, vascular graft tis, vasculitis, inflammatory bowel disease, sarcoidosis, and infection, and metastatic infectious disease; imaging of fever of unknown origin. noninfectious inflammatory diseases such as rheumatoid Key Words: infectious disease; PET; SPECT; inflammation; arthritis (RA), vasculitis, inflammatory bowel disease radionuclide imaging (IBD), and sarcoidosis; and fever of unknown origin J Nucl Med 2010; 51:1937–1949 (FUO). Imaging of other inflammatory diseases such as DOI: 10.2967/jnumed.110.076232 infection of joint prostheses has been specifically covered by recent reviews and is therefore not the subject of this paper. Apart from clinical examination, the diagnosis of in- IMAGING TECHNIQUES flammatory diseases usually requires laboratory tests and Imaging techniques for the detection of inflammation include ultrasonography, CT, MRI, endoscopic techniques, PET, planar scintigraphy, and SPECT. All these techniques Received Jun. 8, 2010; revision accepted Oct. 12, 2010. For correspondence or reprints contact: Martin Gotthardt, Department of have specific advantages and disadvantages. To better Nuclear Medicine, Radboud University, Nijmegen Medical Centre, P.O. Box understand the roles of these modalities in relation to the 9101 6500 HB Nijmegen, The Netherlands. E-mail: [email protected] nuclear medicine techniques, it is important to be aware of COPYRIGHT ª 2010 by the Society of Nuclear Medicine, Inc. their respective advantages and disadvantages. INFLAMMATION IMAGING • Gotthardt et al. 1937 Ultrasonography is widely available, quick, inexpensive, different mechanisms. The first mechanism is uptake into and not associated with radiation exposure. It has an inflamed tissue as a result of increased metabolism, either excellent spatial resolution reaching below 1 mm and can of inflammatory cells (18F-FDG, as a glucose analog be used to obtain functional information to a limited extent reflecting the energy demand of inflammatory cells) or of (e.g., blood flow by Doppler ultrasonography). The dis- tissue-specific cells with increased activity as a reaction to advantages are that the results are highly operator-depend- inflammation (99mTc-hydroxymethylene diphosphonate and ent, penetration and reflection of the sound waves in tissue 99mTc-methylene diphosphonate, reflecting the activity of may be hindered by gas (bowel) or dense structures (bone), osteoblasts as the active response of bone to inflammation). and structures deep within the body may be difficult to The second mechanism is unspecific accumulation in the visualize because the image quality suffers from the longer site of inflammation as a result of increased blood flow and wavelengths used for deep imaging. enhanced vascular permeability (albumin, IgG). In the case CT is highly reproducible, has an excellent spatial of labeled activated leukocytes, the uptake mechanism is resolution, and, although more expensive than ultrasonog- specific migration to the site of inflammation. Finally, 67Ga raphy, is still relatively inexpensive. The disadvantages are binds to transferrin, with the complex being extravasated at exposure of the patient to radiation and the lack of func- sites of inflammation because of increased vascular perme- tional information. Furthermore, the use of contrast medium ability and then being transferred to locally present lacto- to enhance image contrast may be limited or impossible in ferrin. Most radiolabeled agents would accumulate at sites patients with impaired renal function or previous allergic of infection if the local blood flow and the vascular perme- reactions. ability were increased, but local binding also plays a role as MRI is also characterized by a high resolution, has some exemplified by 67Ga-citrate. Bisphosphonates are another potential to obtain functional information, and causes no example of several mechanisms playing a role in the accu- radiation exposure. It has also become widely available but mulation of a radiotracer. Bisphosphonates show increased is prone to movement artifacts because of the relatively uptake at sites of inflammation on early images taken long examination time. Because of the long imaging times directly after injection of the radiopharmaceutical (arterial and the considerable exposure to noise, MRI is not con- phase, as a result of increased blood flow) and a few venient for patients. Furthermore, there are limitations to minutes after injection (blood-pool phase, as a result of the scanning of patients with pacemakers, implants, and increased vascular permeability in combination with in- other devices, and the procedure is relatively expensive. creased blood flow) and on the delayed images several Although PET and SPECT have a limited spatial hours after injection (static phase, as a result of increased resolution (PET down to 3–5 mm; SPECT down to 8–10 bone metabolism reflecting osteoblastic activity at sites of mm), their asset is high contrast resolution, offering func- inflammation) (Table 1). tional and molecular information with high sensitivities in the nano- or picomolar range (PET . SPECT). The radiation IMAGING OF INFECTIOUS DISEASES exposure is mostly low but, dependent on the radiotracer Osteomyelitis used, may reach the radiation exposure of an abdominal Three-phase bone scanning with 99mTc-hydroxymethy- CT scan. lene diphosphonate or 99mTc-methylene diphosphonate has long been used as the standard method for the detection RADIOPHARMACEUTICALS of osteomyelitis. Bone scintigraphy has a high sensitivity Radiopharmaceuticals for imaging of inflammatory dis- exceeding 80% and a limited specificity reaching up to 50% ease should be highly sensitive (apart from having general (Fig. 1) (1,2). The limited specificity can be explained by characteristics such as easy preparation, wide availability, uptake of the radiopharmaceutical at all sites of increased and low cost). In addition, in an ideal situation radio- bone metabolism irrespective of the underlying cause. pharmaceuticals would also be able to distinguish between However, if combined SPECT/CT is performed, the speci- infectious and sterile inflammation. A wide variety of ficity increases considerably