Timely identification and localization of infectious and inflammatory processes is a critical step toward appropri- ate treatment of patients with known or suspected of such disorders. Radiologic techniques including computed to- mography, magnetic resonance imaging, and ultrasonog- raphy have been frequently utilized for this purpose.
However, these techniques rely solely on structural changes, and therefore discrimination of active infectious and inflammatory processes from alterations following surgery or other intervention remain difficult with these modalities. Also, infectious and inflammatory disorders cannot be detected in the early stages of their develop- ment because of the lack of substantial structural de- rangements, which render anatomic techniques insensitive for early diagnosis. Furthermore, these tech- niques, based on current standards, provide information on only a limited part of the body. However, because of advance made in recent years, it becomes feasible to scan the entire body within a short period of time.
Conventional nuclear medicine modalities, such as
67Ga imaging and labeled leukocyte studies, have been useful in diagnosing some infectious disease and have con- tributed significantly to the management of such patients during the past three decades. However, these techniques suffer from many shortcomings. Recent developments in the field have substantially improved the ability of the ra- diotracer imaging techniques to detect infectious disease.
These new methods are based on utilizing radiolabeled chemostatic peptides (1), radiolabed liposomes (2), avidin-mediated agents (3–5), radiolabeled antibodies (6, 7), radiolabeled antibiotics (8), and positron-emitting compounds, such as [
18F]fluorodeoxyglucose (FDG). In this chapter, we discuss the evolving role of positron emission tomography (PET) in this setting.
FDG is transported into cells by glucose that is trans- ported and phosphorylated by hexokinase to FDG-6- phosphate. Phosphorylated FDG is trapped inside cells for a prolonged period of time. The deoxy-substitution pre-
vents further metabolism of FDG and, therefore, over time monophosphorylated product accumulates in the tissue (9). Multiple factors influence the degree of uptake and in- tracellular accumulation of FDG. High level of expression of glucose transporters is known to be an important factor for facilitating FDG uptake in tumor cells. Tumor cells show increased expression of glycolytic enzymes, includ- ing hexokinase, and decreased expression of glucose-6- phosphatase, compared to normal cells (10, 11).
Consequently, high levels of FDG-6-phosphate are pro- duced and retained in malignant tissues.
FDG is not a tumor-specific tracer. Due to enhanced glycolytic activity, activated inflammatory cells such as neutrophils and macrophages also have increased FDG uptake, which results in high FDG concentration of this agent at sites of inflammation and infection (12–15). FDG rapidly accumulates at sites of bacterial infection and in reactive lymph nodes and results in high contrast between the affected and noninvolved tissues (16). There is evi- dence that inflammatory cells also have increased expres- sion of glucose transporters when they are activated (17, 18). Acute human immunodeficiency virus (HIV) infec- tion leads to increased expression of glucose transporters at high levels and a corresponding increase in glucose metabolic activity (19). It is possible that the metabolism of glucose and FDG uptake by inflammatory cells is more complicated than in malignant cells. For example, there is evidence that numerous cytokines and growth factors, whose levels are often increased during infection, may dramatically affect glucose uptake by inflammatory cells (20–24).
The hierarchy for the degree of FDG uptake by resting inflammatory cells is as follows: neutrophils greater than macrophages greater than lymphocytes (25), which would indicate that infectious or inflammatory sites where neu- trophils or macrophages dominate are more likely to be visualized by FDG-PET than those dominated by lympho- cytes. However, in spite of low levels of FDG uptake by
30320
Evolving Role of FDG-PET Imaging in the Management of Patients with Suspected Infection and Inflammatory
Disorders
Hongming Zhuang and Abass Alavi
lymphocytes in the resting state, glucose metabolic activ- ity of these cells can increase dramatically upon stimula- tion. Using a mouse skin transplantation model, Heelan et al. (26) found that FDG uptake was 1.5 to 2 times higher in allografts than in syngeneic grafts and that the increase in uptake correlated with the levels of T-cell infiltrate seen histologically. Furthermore, FDG-PET images of simian immunodeficiency virus (SIV)-infected animals were readily distinguishable from those of an uninfected control cohort and revealed a pattern consistent with widespread lymphoid tissue activation. Areas of elevated FDG uptake on the PET images correlated well with pro- ductive SIV infection using in situ hybridization as a test for virus replication. These data suggest that the FDG-PET method can be used to evaluate the presence and the state of inflammatory reaction in infected tissues in vivo, thereby avoiding invasive procedures such as biopsy (27).
FDG-PET imaging has been used with great success in the management of patients with a variety of malignan- cies. In contrast, reports of the utility of FDG-PET in de- tecting and characterizing infectious diseases are limited in the literature. FDG accumulates in a variety of infec- tious and inflammatory sites, including abscesses in abdomen (28), brain (29), lung (30), kidney (31), tubo- ovarian (32, 33), inflammatory pancreatic disease (34), lobar pneumonia (35, 36), sarcoidosis (37, 38), os- teomyelitis (7, 39), tuberculosis (40, 41), mastitis (42), and infectious mononucleosis (43). The accumulation of FDG in sites of infection or inflammation is one of the major causes of false-positive results when this imaging tech- nique is used in oncology. On the other hand, high accu- mulation of FDG at sites of infection provides an opportunity to use FDG-PET imaging for the management of patients with suspected or known infection. In an early report with a total of 24 patients with various infectious lesions, FDG-PET achieved a sensitivity of 92% and a specificity of 100% (44).
Imaging Protocols for Infection and Inflammation
Currently, there is no consensus about an optimal FDG- PET imaging protocol for the assessment of infectious and inflammatory processes because of limited experience with this application. Many centers employ the same pro- tocol that is in place for assessment of patients with cancer. However, because of inherent biologic differences between the two processes, imaging procedures may need to be adjusted for optimal results.
The optimal time interval between the injection of FDG and data acquisition is not well established when FDG- PET is used to examine patients with a malignant disease.
Most centers initiate imaging 60 min following the admin- istration of FDG. Some authors believe that a short 30- min dynamic data acquisition is as effective as longer
acquisition time in the diagnosis of lung cancer (45). On the other hand, many publications suggest that delayed imaging up to several hours from the time of injection of FDG would result in increase of sensitivity of the tech- nique in the diagnosis and management of patients with several types of cancer (46–59). In contrast, in infection imaging, there is strong evidence that the interval between injection and data acquisition can be substan- tially shortened without an adverse effect on the sensitiv- ity of the technique in detecting the site of abnormalities.
Early experiments in animal models demonstrated that FDG uptake by the inflammatory cells increases gradu- ally until 60 min following injection, and then it reaches a plateau and then declines thereafter. This observation has been confirmed in later studies. Therefore, the time in- terval between the administration of FDG and data acqui- sition could be shortened to less than 60 min for this indication, but this protocol requires validation with future studies.
The effect of serum glucose levels on the sensitivity of FDG-PET imaging in the diagnosis of infection is poorly defined at this time. It is well known that hyperglycemia results in significantly reduced FDG uptake by malignant lesions (60). As a result, hyperglycemia can lead to false- negative findings in a variety of malignancies, including bronchial carcinoma (61), head and neck cancer (62), and pancreatic neoplasias (63). To reduce serum glucose levels before to FDG-PET imaging, patients with cancer are in- structed to fast for several hours. Also, in these patients, their serum glucose concentration is assessed before FDG is administered to make certain that the levels are optimal for this purpose. Based on recent data generated in our laboratory, inflammatory cells differ significantly from malignant cells with regard to the time course of FDG uptake and its retention, as measured by in vitro tech- niques. There is evidence that hyperglycemia may not ad- versely affect FDG uptake by inflammatory lesions, which is in contrast to malignant lesions (64). Animal experi- ments have shown that during septic shock glucose me- tabolism in macrophage-rich tissues remains elevated regardless of serum glucose level (65). In a clinical study in patients with chronic pancreatitis, Diederichs et al. (63) found that the average standardized uptake value (SUV) of the pancreatic tissue obtained in hyperglycemic pa- tients was slightly higher than that in euglycemic patients, although the difference was not statistically significant.
Most tumor cells have been shown to exhibit increased glycolytic activity and, therefore, have low glycogen storage and fully depend on extracellular glucose supply.
In contrast, inflammatory cells are capable of mobilizing
their intracellular glycogen storage to produce glucose
during periods of low plasma glucose. One example is the
process of granulocyte phagocytosis, which often occurs
in a hypoglycemic environment and depends heavily on
glycogen storage (66). Therefore, the effects of glucose
concentration on FDG uptake appear to be negligible in
FDG-PET imaging to detect inflammation.
In addition, cytokines released during the process of inflammation and infection also modulate FDG uptake by inflammatory cells. One example is platelet-activating factor, which is an important cytokine involved in a variety of inflammatory and infectious disorders (24, 67, 68). In animal experiments, it has been shown that platelet-activating factor can cause hyperglycemia (69, 70). In addition, platelet-activating factor increases glucose uptake by polymorphonuclear leukocytes and monocytes in such a hyperglycemic environment (70).
Similarly, granulocyte colony-stimulating factor (G-CSF)- treated rats revealed enhanced glucose uptake by several organs, which was not affected by changes in plasma glucose or insulin concentrations (20). This regulatory effect of cytokines and growth factors on FDG uptake would be very small in malignant cells because of their relatively autonomous nature. Accordingly, fasting may not be necessary when FDG-PET is used for the assess- ment of infection. If this phenomenon can be confirmed in clinical settings, it would simplify patient preparation considerably when FDG-PET imaging employed to detect inflammatory processes. This change would be of espe- cially great importance in examining diabetic patients, who are prone to have frequent infections.
Clinical Applications
Chronic Osteomyelitis
When bone architecture has been altered by previous trauma, surgery, or soft tissue infection, it is often difficult to exclude chronic osteomyelitis and to differentiate soft tissue infection from osseous infection by imaging tech- niques (71). Bone scintigraphy plays an important role in
the diagnosis of osteomyelitis, especially in an otherwise intact bone. Three-phase bone scanning has good sensi- tivity for detecting infection, but its specificity is relatively low (72).
67Gallium imaging in conjunction with bone scintigraphy has been used to distinguish infections from other processes, but this combination study has an accu- racy of only 70% (73). When combined with bone scan- ning, labeled-leukocyte imaging has a good accuracy for diagnosing chronic osteomyelitis in the appendicular skeleton (71, 73). However, in chronic osteomyelitis of the axial skeleton and other sites with high concentration of red marrow, labeled white blood cell (WBC) images of in- fection frequently appears as areas of decreased activity, which is nonspecific and is seen in inactive process such as fibrosis, surgical changes, fractures, necrosis, degenera- tive disease, and hematologic disorders (74–76). For these reasons, WBC imaging of sites of infection in the axial skeleton and in areas with hematopoietic activity has an accuracy of 53% to 76% and therefore is of limited value (77).
FDG-PET imaging has proven to be useful in the diag- nosis of osteomyelitis (Figures 20.1, 20.2), with a sensitiv- ity of 95% to 100% and specificity of 85.7% to 95% in a relatively small number of patients (7, 39, 78). According to these reports, FDG-PET is able to correctly diagnose chronic osteomyelitis when both MRI and antigranulocyte antibody imaging appear negative. In a study of 51 pa- tients, Guhlmann et al. (7) noted that FDG-PET imaging was superior to combined 99mTc-labeled monoclonal antigranulocyte antibody imaging and bone scintigraphy in the diagnosis of chronic osteomyelitis. Meller et al.
compared the efficacy of labeled-leukocyte imaging and FDG-PET with coincident camera in the evaluation of chronic osteomyelitis. They reported that labeled-leuko- cyte imaging was true positive in 2 of 18 regions, true neg- ative in 8 of 18 regions, false negative in 7 of 18 regions,
TRANSVERSE SAGITTAL CORONAL
Figure 20.1. FDG-PET images of the femur of a 41-year-old man who was involved in a motor vehicle accident and was suspected of suffering from osteomyelitis of the right distal femur. Increased glucose metabolism in the marrow space of the right distal femur is seen (arrow). The site of inflammatory reaction extends outward from the distal femur to the lateral fascia of the right thigh. [From Zhuang H, Duarte PS, Pourdehand M, et al. Exclusion of chronic osteomyelitis with F-18 fluorodeoxyglucose positron emission tomographic imaging. Clin Nucl Med 2000;25(4):281–284.]
and false positive in 1 of 18 regions. In contrast, FDG imaging was true positive in 11 of 11 regions and true neg- ative in 23f of 25 regions (79). FDG-PET was found to be especially useful for the evaluation of the axial skeleton. In a study of 32 patients with suspected vertebral os- teomyelitis, De Winter et al. (80) reported sensitivity, specificity, accuracy, and interobserver agreement of 100%. When the results of FDG-PET imaging were com- pared with those of the combined bone and white blood cell scintigraphy, FDG-PET was significantly more accu- rate.
Particularly, FDG-PET imaging can correctly distin- guish chronic osteomyelitis from a healing bone reaction (81). It is known that there is frequently increased FDG accumulation in the acute fracture site (82, 83) (Figure 20.3). However, the increased FDG activity in the fracture sites is usually transient. It is uncommon to note significant FDG activity at the fracture sites after a few months if no complications have followed the incident (84, 85). Therefore, the history of fracture several months earlier is unlikely to affect the diagnosis of osteomyelitis by FDG-PET. This argument was confirmed by an animal experiment by Koort et al. (86) in which they found that uncomplicated bone healing in rabbits was associated
with a temporary increase in FDG uptake at 3 weeks, which mostly disappeared by 6 weeks. In the experimental animals, localized osteomyelitis resulted in an intense continuous uptake of FDG, the degree of which was higher than that of healing bones at both 3 weeks and at 6 weeks.
This pattern differs from that of bone scintigraphy, where a positive result may indicate either an active infection or a reparative process following successful treatment (87)].
The high spatial and contrast resolution of FDG-PET imaging may also permit differentiation of osteomyelitis from infection of soft tissue surrounding the bone. FDG- PET imaging can provide definitive evidence and the exact location of sites of infection within a few hours of tracer administration, compared to 24 to 48 h for
67Ga or labeled-leukocyte imaging. Because of the high sensitivity of FDG-PET imaging in detecting infection, a negative study essentially rules out osteomyelitis (39). In contrast, caution should be exercised in the interpretation of a pos- itive FDG-PET, as its predictive value is lower than that of a negative result. FDG-PET is a cost-effective alternative to the combined use of three-phase bone scanning, leuko- cyte scintigraphy, and bone marrow imaging in this setting and should be considered as the study of choice for optimal management of such patients.
TRANSVERSE SAGITTAL
Lt Lateral Anterior
CORONAL Gallium
MDP
FDG
Figure 20.2. FDG-PET images of a 33-year-old man with left ear malignant otitis (arrows) caused by Pseudomonas aeruginosa. Corresponding bone scan and 67gallium images show an extensive area of abnormal activity whereas FDG-PET localizes the infection to a considerably smaller area.
Infections Associated with Prostheses
The success of prosthetic joint implant surgery has greatly improved the quality of life for individuals suffering from degenerative and other joint diseases. The number of lower limb arthroplasties performed in the United States has increased dramatically over the past two decades.
More than 10% of patients will develop discomfort or pain at some time point following arthroplasty. The majority of these symptoms are the result of mechanical failure or loosening, while only a small fraction is caused by super- imposed infection. Infection occurs in fewer patients fol- lowing initial lower limb arthroplasty, but the incidence can be as high as 30% following prosthesis revisions (88, 89). It is crucial that the diagnosis of infected prosthesis is established before the patient is subjected to further surgi- cal intervention. Multiple tests, which often include X-ray radiography, bone scanning, labeled-leukocyte scintigra- phy, measurement of C-reactive protein, and joint aspira- tion followed by bacterial culture, are frequently required to establish the diagnosis of infection (90). Among nuclear medicine studies, bone and
67Ga scans were first used to detect periprosthetic infections but did so with relatively low sensitivity (91, 92). Some authors have sug- gested that labeled-leukocyte scanning (93) can provide high sensitivity and specificity in this setting, especially when it is combined with
99mTc-sulfur colloid bone marrow imaging (94,95). However, the reported accuracy of this technique has varied and no consensus has been established concerning its utility. In a study by Scher et al.
(96) in which 153 labeled-leukocyte scans were performed on 143 patients with painful prostheses, the authors re-
ported a sensitivity of 77%, a specificity of 86%, and posi- tive and negative predictive values of 54% and 95%. They concluded that labeled-leukocyte scan should not be rec- ommended routinely for evaluating periprosthetic infec- tion because of the complexity of the procedure, the cost associated with this study, the need for two separate visits separated by at least 24 h, and unsatisfactory accuracy.
FDG-PET has proved to be an effective modality in the diagnosis of infection associated with lower limb arthro- plasty. Clinical studies have demonstrated an overall sen- sitivity of 90% to 100% and a specificity of 81% to 89% for FDG-PET (97, 98). Based on some preliminary data, it appears that this technique has a higher accuracy in the diagnosis of painful hip prostheses than that in knee pros- theses (98). In a study of 36 knee prostheses and 38 hip prostheses, the sensitivity, specificity, and accuracy of FDG-PET for detecting infection associated with knee prostheses were 90.2%, 72.0%, and 77.8%, respectively. In comparison, the sensitivity, specificity, and accuracy of FDG-PET for detecting infection associated with hip pros- theses were 90.0%, 89.3%, and 89.5% (98). In contrast to computed tomography (CT) and magnetic resonance imaging (MRI), FDG-PET is not hindered by metallic im- plants that are commonly used for orthopedic procedures (99, 100). In addition, bone marrow uptake of FDG is minimal in the elderly population who are candidates for this surgical procedure. The higher spatial resolution of FDG-PET compared to conventional nuclear medicine imaging modalities enable small and subtle lesions to be detected (Figure 20.4).
Accurate diagnosis of periprosthetic infection would require defining appropriate criteria for distinguishing in-
Figure 20.3. FDG-PET/CT images of a patient who sustained a severe trauma to the chest wall 3 weeks previously. Increased FDG activity is shown in the left posterior chest wall, and CT shows a recent fracture (arrows). These findings were interpreted to represent a recent fracture with inflammatory reaction resulting from the healing process.
Coronal
Figure 20.4. Coronal FDG-PET images of a 63-year-old man with painful right hip prosthesis. Infection (arrowheads) at the bone–prosthesis interface and a fistula (long arrows) are clearly demonstrated on these images. (Reprinted by permission of the Society of Nuclear Medicine from Zhuang H, Duarte PS, Pourdehnad M, et al. The promising role of 18F-FDG PET in detecting in- fected lower limb prosthesis implants. J Nucl Med 2001;42:44–48, Figures 2 and 4.)
a
c
b
d
Figure 20.5. (a) Coronal FDG-PET images of a 72-year-old woman with infected hip prosthesis. Periprosthetic infection is identified on the right (arrowheads). (b) Coronal FDG-PET images of a 76-year-old woman with bilateral hip prostheses. Both nonspecific uptake in the head and neck region (thin arrows) and activity suggestive of infection along the bone–prosthesis interface (short arrow) are shown. (c) Coronal FDG-PET images of a 78-year-old man with painful left hip prosthesis. Arrowheads indicate periprosthetic infection. (d) Coronal image of a 76-year-old woman with bilateral hip prostheses. FDG uptake is noted only around the neck of the right prosthesis (arrows). Revision arthroplasty confirmed that there was no infection. (Reprinted by permission of the Society of Nuclear Medicine from Zhuang H, Duarte PS, Pourdehnad M, et al. The promising role of 18F-FDG-PET in detecting infected lower limb prosthesis implants. J Nucl Med 2001;42:44–48, Figures 2 and 4.)
fection from aseptic loosening. In recent reports where
“increased uptake compare to adjacent, presumably normal activity” was used as the evidence for infection that may be associated with arthroplasty, FDG had a sen- sitivity of 100% but very low specificity (101, 102). This finding can be partially attributed to the fact that these in- vestigators utilize a coincidence scintillation camera to acquire PET images of the hips (103). This type of instru- ment usually provide images that are somewhat subopti- mal for definitive diagnosis. Based on our experience, in hip prostheses, increased FDG uptake must be present along the interface between the prosthesis and bone to be regarded as positive for infection.
It is very common to note significantly increased FDG uptake around the neck and/or head segment of the pros- thesis soon after arthroplasty, which may last indefinitely.
The SUV of these abnormalities can be as high as 7.0 (Figures 20.5, 20.6). However, without increased FDG uptake along the bone–prosthesis interface, the diagnosis of infection can be excluded as the cause of painful pros- thesis. Therefore, increased FDG uptake along the inter- face strongly suggests infection (Figure 20.5). Manthey et al. (104) suggested that high FDG uptake in the bone pros- theses interface should be considered as evidence for in- fected implant whereas an intermediate level of uptake is suspect for loosening, and that uptake only in the synovia would be considered as synovitis. For knee prostheses, these diagnostic criteria result in a high percentage of false-positive results (98, 105).
Another possible source of error in characterizing painful prostheses with FDG-PET imaging is postsurgical change following arthroplasty. For most surgical proce- dures, the effects of the operation may produce increased FDG uptake for up to 6 months (106). However, non- specific increased FDG uptake caused by uncomplicated hip arthroplasty may persist for a indefinite period of time (Figures 20.6, 20.7). The pattern of nonspecific FDG
uptake in uncomplicated arthroplasty is the same as that noted in loosening: increased FDG uptake around the head or neck of the prosthesis. As a result, the diagnosis of periprosthetic infection is not adversely affected by postsurgical changes, and the presence of infection can be reliably detected in spite of postsurgical pattern of FDG uptake in most patients (107).
Last, when a painful prosthesis is evaluated for infec- tion, nonattenuation-corrected images should be utilized for this purpose. It is known that attenuation correction result in reconstruction artifacts that may be misinter- preted as representing sites of infection, and this is espe- cially true when integrated PET/CT is employed for this purpose (Figure 20.8).
Acquired Immunodeficiency Syndrome
Patients with acquired immunodeficiency syndrome (AIDS) have increased risk of developing a variety of op- portunistic infections. These infections often manifest with nonspecific symptoms and sign and present with no localizing features. In a landmark study involving 57 AIDS patients by O’Doherty et al. (108), FDG-PET successfully localized the sites of a variety of infections caused by Pseudomonas, Mycobacterium avium-intracellulare, Mycobacterium tuberculosis, cryptococcus, and staphylo- coccus. In addition, FDG-PET imaging also successfully identified several sites of malignant lesions. Overall, the sensitivity and specificity of FDG-PET imaging were 92%
and 94%, respectively, in detecting either infectious or malignant disorders in patients with AIDS (108).
The first report by Hoffman et al. (109) noted that central nervous system lymphoma is metabolically active and appears positive on FDG-PET images. In contrast, FDG uptake in lesions caused by toxoplasmosis is sub- stantially low compared that in the central nervous system
CORONAL SAGITTAL
Figure 20.6. Images of a patient with left painful hip prosthesis. The arrows point to the sites of increased FDG uptake. Because FDG uptake was not de- tected at the bone–prosthesis interface, presence of infection was ruled out based on FDG-PET criteria. Revision arthroplasty confirmed loosening.
lymphoma. Similar results have been reported by other investigators (108, 110). One exception is progressive multifocal leukoencephalopathy, which is difficult to di- agnose by FDG-PET imaging alone (108, 110).
Quantitative assessments of sites of FDG uptake have re- vealed that the SUV of toxoplasmosis lesions is significantly (P less than 0.05) lower than that of the sites of lymphoma, with no overlap between the two groups (108, 111).
PET has also been used in animal studies to image the metabolic changes that result from simian immunodeficiency virus (SIV) infection at the affected sites. PET images in SIV-infected animals were easily dis- tinguishable from those of uninfected controls and re- vealed a pattern consistent with widespread lymphoid tissue activation. Regions of elevated FDG accumulation
corresponded to the sites of active SIV replication (27). In a similar study using rhesus macaque monkeys infected by SIV 89.6PD, Wallace et al. (112) showed that FDG-PET imaging revealed a distinct pattern of lymphoid tissue ac- tivation. Increased tissue FDG uptake preceded fulminant virus replication at these sites. These data raise the possi- bility of using FDG-PET to evaluate the distribution and activity of immunodeficiency virus in humans, thus providing a potential basis for early detection of AIDS infection.
Fever of Unknown Origin
The causes of fever of unknown origin (FUO) are numer- ous. Patients presenting with FUO can be divided into two
a b c d
Figure 20.8. FDG-PET/CT images of an asymptomatic patient with a right hip prosthesis. CT image (a), as predicted, showed significant artifacts due to implanted metal prosthesis.
Attenuation-corrected image (b) and fusion image (c) show intense FDG activity in the region of the head of prosthesis with a standardized uptake value (SUV) of 8. In contrast, on the image without attenuation correction (d), no such activity is detected.
3 month 6 month 11 month
Figure 20.7. Persistently increased FDG accumulation after left hip arthroplasty in an asymptomatic patient who was examined at 3, 6, and 11 months postsurgery.
broad groups: those with occult infection and those with neoplasm or autoimmune disease.
67Ga scans and labeled- leukocyte imaging have been commonly used in such clin- ical settings. Labeled-leukocyte scanning is generally preferable in patients with suspected infection, whereas
67
Ga scanning is more effective in patients with possible tumor or autoimmune diseases. Because many underlying causes of FUO do not stimulate a neutrophilic infiltrate, noncellular tracers such as
67Ga, FDG, or labeled human immunoglobulin may be preferable for this purpose.
In most situations,
67Ga imaging is considered prefer- able to labeled leukocytes for its ability to image both in- fectious or inflammatory and malignant processes (113).
However, the physical quality of
67Ga images is poor because of the low spatial resolution of the images gener- ated and the low contrast between the affected sites and the normal structures. When abdominal infection is sus- pected, physiologic accumulation of
67Ga in bowel sub- stantially reduces the specificity of this technique.
FDG-PET can be a useful tool for the evaluation of FUO (Figure 20.9) and may replace
67Ga and labeled-leukocyte imaging altogether in the future. One advantage of FDG- PET imaging is its ability to detect both infectious/inflam- matory lesions and malignant lesions with high sensitivity and specificity. In addition to infection and malignancy, FDG-PET can also detect rare diseases that may be present with FUO. For example, in childhood sarcoidosis, a disease with multisystem organ involvement, initial pre- sentation as FUO is relatively common. It is well known that sarcoidosis can be readily detected by FDG-PET imaging (37, 38, 114). Similarly, several investigators have also shown the utility of FDG-PET for detecting vasculitis (115–120), which is another possible cause of FUO.
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder that may result in life-threatening infections. In a study of five children with CGD and signs of infection of unknown origin, PET imaging detected 102 foci of infection that were confirmed by bacteriologic and histologic findings. CT imaging de- tected only 49 of these sites. In addition, PET excluded active infection at 20 sites that appeared abnormal on CT imaging (121). A recent study compared FDG-PET and
67
Ga imaging in detecting the underlying causes of FUO.
In this study, the sensitivity and specificity of FDG-PET were 84% and 86%, respectively, compared to 67% and 78% for
67Ga single photon emission computed tomogra- phy (SPECT) (122). Overall, whole-body FDG-PET de- tected the cause of FUO in more than half the patients.
Monitoring Response to Therapy
The potential utility of FDG-PET for treatment monitor- ing stems from its ability to quantitate FDG uptake in se- quential studies. This approach is successfully employed in monitoring patients with a variety of malignancies in- cluding lymphoma. Schmitz et al. (123) noted that FDG- PET imaging was able to assess the state of disease activity in a case of tuberculous spondylitis and to differentiate between bone and soft tissue infection. FDG-PET imaging has also been used to monitor treatment of aspergillosis (124, 125). It has been reported that FDG-PET imaging is an effective method of evaluating the efficacy of chemotherapy in alveolar echinococcosis by demonstrat- ing the resolution of abnormal metabolic activity with successful treatment. Parasitic viability in alveolar echinococcosis cannot be assessed by conventional imaging, and the long-term treatment of the condition is very costly. FDG-PET may also be useful for timely detec- tion of relapse of echinococcosis after initial treatment (126). Similarly, Mycobacterium avium-intracellulare in- fection is a common complication in immunocompro- mised patients and monitoring its treatment is often difficult. O’Doherty et al. (108) reported that following ef- fective therapy of M. avium-intracellulare infection, there was reduction in FDG uptake by the lesions. We have em- ployed sequential FDG-PET imaging in patients with in- fection and inflammatory disorders such as sarcoidosis (Figure 20.10).
Conclusions
Whole-body FDG-PET imaging is clearly superior to the anatomic imaging techniques such as contrast-enhanced
CHEST X-RAY CORONAL SAGITTAL TRANSVERSE
Figure 20.9. FDG-PET images of a patient who had fever of unknown origin (FUO) revealed a large focus of FDG accumulation in the posterior aspect of left upper lung (black arrows), which corresponded to the site of opacity on the follow-up chest X-ray (white arrow). These findings were interpreted to represent a site of inflammation and may represent the source of FUO.
Pre-treatment Post-treatment Normal
Figure 20.10. Pre- and posttherapy FDG-PET scans (attenuation-corrected projection image) of a patient with known pulmonary Mycobacterium avium-intracellulare infection re- vealed significant reduction of activity following treatment. Attenuation-corrected projection image from a normal subject is also shown for comparison.
Figure 20.11. In this 21-year-old woman with Chlamydia trachomatis pelvic inflammatory disease, FDG-PET identified the infected site (arrows) whereas 67Ga SPECT appeared within normal limits. (From Meller J, Altenvoerde G, Munzel U, et al. Fever of unknown origin:
prospective comparison of [18F]FDG imaging with a double-head coincidence camera and gallium-67 citrate SPET. Eur J Nucl Med 2000;27(11):1617–1625.)
Ga–67–Citrate
F–18–FDG
CT and MRI, which primarily rely upon the presence of hyperemia, increased perfusion, and increased capillary permeability as evidence for inflammation (127). FDG- PET imaging also has higher sensitivity and specificity in the evaluation of infection compared to
67Ga and other conventional scanning technique and it is expected to replace those techniques eventually as the study of choice for detection and localization of infection (122) (Figure 20.11).
FDG-PET also has advantages over labeled-leukocyte imaging. Detection of infection by the labeled-leukocyte method depends on the migration of labeled neutrophils to the sites of infection, whereas FDG-PET can demon- strate increased glucose uptake in cells that are already present at the inflammatory lesion. Also, labeled-leuko- cyte imaging is only be effective when the predominant cellular reaction to infection involves neutrophils rather than lymphocytes.
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