PET > PET Infection_Inflammation

PET in Infection Imaging:

General:

PET imaging has several advantages over convention nuclear infection imaging including tomographic scans with excellent spatial resolution and same day imaging [11]. FDG PET appears to be very good for the evaluation of suspected infection of the musculoskeletal system. Activated inflammatory cells demonstrate increased expression of glucose transporters- GLUT1 and GLUT3 [10,33]. The physiologic basis of FDG PET in the identification of infection is likely related to the respiratory burst that neutrophils and monocytes experience when exposed to proinflammatory cytokines (e.g., granulocyte?macrophage colony stimulating factor, interleukin-8, and interleukin-6), with the resulting metabolization of large amounts of glucose (ie: inflammatory cells at sites of infection show increased glycolytic activity) [1,2]. Increased splenic activity can be seen in patients with underlying infections- presumably related to increased glucose utilization [10]. However, FDG imaging cannot discriminate between and infectious and an inflammatory process [38].

Antibiotic treatment does not appear to significantly impact on the diagnostic accuracy of FDG PET imaging for evaluaiton of infection, however, the SUVmax in sites of infection have been shown to be slightly lower in these patients compared to untreated patients (although not statistically significant) [48]. In animal models, both hyperglycemia and hyperinsulinemia have been shown to decrease FDG uptake at sites of infection and inflammation [15].

The major indications for ¹⁸F FDG PET/CT in infection and inflammation are sarcoidosis, peripheral bone osteomyelitis (nonpostoperative, nondiabetic foot), suspected spine infection (spondylodiskitis or vertebral osteomyelitis, nonpostoperative), evaluation of FUO, evaluation of metastatic infection and of high-risk patients with bacteremia, and primary evaluation of vasculitides (such as giant cell arteritis) [33].

It is presently unclear if FDG PET offers a significant advantage over labeled WBC imaging for diabetic foot infection, joint prosthesis infection, vascular prosthesis infections, inflammatory bowel disease, or endocarditis [33].

False positive exams have been reported in up to 10% of patients and are associated with chronic granulocytic or reactive post surgical changes, inflammatory processes, Charcot osteoarthropathy, fractures, and retroperitoneal fibrosis [48].

¹⁸F- FDG-labeled white bloods have also be evaluated for use in infection imaging [9].

Metallic implants:

About 400,000 hip and knee arthoplasties are performed annually in the United States [7]. Infection after primary implantation occurs in approximately 1% of primary hip arthroplasties and 2% of primary knee arthroplasties [7]. The rate of infection following revision surgery is higher- about 3% for hip and 5% for knee replacements [7]. Approximately one-third of infections develop within 3 months of surgery, another third within 1 year, and the remainder more than 1 year after surgery [7]. FDG PET imaging has been used to evaluate for infected orthopedic prostheses and can assess for the presence of both acute and chronic infectious processes [1]. Advantages of FDG PET imaging over conventional imaging include: 1- FDG accumulates within the site of infection within 60 minutes which provides for rapid patient evaluation; 2- PET imaging has a much higher spatial resolution compared to single photon techniques which allows better distinction between soft-tissue and osseous infection; and 3- FDG PET imaging is less expensive than leukocyte-based labeling techniques [1].

When evaluating FDG PET/CT imaging for prosthetic infection, careful attention to the non-attenuation corrected images is recommended, because there can be false elevated activity on attenuation corrected images due to beam-hardening artifact on the CT images [49]. Initially, FDG PET imaging had shown great utility for the evaluation of patients with suspected orthopedic prosthesis infections [1]. Sensitivity of up to 100%, specificity of 88-93%, and accuracies of 97% had been reported with low interobserver variability [1]. Recently, lower sensitivities for infected hip prosthesis have been reported (as low as 22%)- with an overall accuracy of only 69% [6]. This is because aseptic loosening and synovitis can also produce a positive PET exam [6,7]. In aseptic loosening, a foreign body granulomatous reaction to polyethylene particles shed by the prosthesis, results in macrophage activation that can produce increased FDG accumulation (despite the absence of neutrophils [42]) [6]. Lower specificity has also been reported (between 9% to 44% depending on the criteria used to define infection) [7].

It is clear that the location of abnormal accumulation is an important element in image interpretation [11]. Intense FDG uptake along the bone-prosthesis interface should be considered positive for infection, mild uptake as suspect for loosening, and uptake only in the soft tissues as evidence of synovitis [11].

Unfortunately, regardless of how the images are interpreted, FDG PET imaging appears to be less accurate than ¹¹¹In-labeled leukocyte/ ^99mTc-sulfur colloid marrow imaging [7].

Scans performed earlier than 6 weeks following surgery may be falsely positive [1]. Other causes of false positive exams are sterile inflammation associated with prosthetic loosening and patient motion between emission and transmission scans [1]. FDG uptake around the head and neck of hip prosthesis can be seen commonly in non-infected prostheses [3], whereas  increased tracer uptake along the interface between the bone and the prosthesis is suggestive of infection [4].

Vascular graft infection:

Vacular graft infection is an uncommon (0.5-5% of cases) complication associated with a high morbidity and mortality [16]. As a rule, most infections occur within a few months of surgery [16]. The clinical presentation is often non-specific [16]. CT and MR imaging may demonstrate a surrounding abscess collection, but the findings are often inconclusive (in one study CT had a sensitivity of 64% [21]) [16].

Synthetic grafts are made either of Dacron or polytetrafluroethylene (Gore-Tex) [36]. Dacron is used mainly in large vessels such as with aortic or aortoiliac surgery, whereas Gore-Tex is used for medium-sized vessels such as the femoral, popliteal, and tibial arteries [36]. Synthetic grafts often induce an aseptic foreign-body chronic low-grade inflammatory reaction  (mediated primarily by macrophages, fibroblasts, and foreign-body giant cells) that can result in tracer uptake along the graft [16,17,21,36]. In one study, high FDG accumulation was identified in 75% of non-infected aortic vascular grafts placed by open surgery (and in one of 4 grafts [25%] placed endovascularly) [17]. In another study, diffuse FDG uptake was found in 92% of non-infected vascular prostheses [32]. The uptake is typically homogeneous, but can be heterogeneous, particularly for Dacron grafts (heterogeneous uptake in a Gore-tex graft should be interpreted with caution) [36]. In general, Dacron grafts also demonstrate a higher level of tracer uptake compared to Gore-Tex grafts and native vein grafts [36]. The uptake in vascular grafts can persist for 10-20 years following surgery and does not change over time of prosthetic grafts [17,36]. However, activity in native vein grafts does decrease over time and persistent activity in a native vein graft should raise the suspicion for infection [36].

When associated with infection, the tracer uptake appears to be more focal, eccentric, and more intense than background graft activity [17]. For best results, PET imaging should be performed at least 2 months following surgery to avoid false-positive results [21].Initial studies suggested that PET/CT imaging could aid in more definitive localization of the site of tracer uptake permitting accurate differentiation of graft infection versus adjacent soft tissue infection [16]. In one study, FDG PET/CT was found to have a sensitivity of 93%, specificity of 91%, a PPV of 88%, and a NPV of 96% [16]. False positive results can occur when the infection is adjacent to or surrounding the graft [16]. In the early phases of healing during the first months following surgery, FDG imaging may give false positive results [15]. .

Osteomyelitis:

Increased FDG uptake can be seen at sites of osteomyelitis [10]. FDG PET has been shown to be superior to ¹¹¹In-labeled leukocyte scintigraphy for diagnosing chronic bacterial osteomyelitis and for establishing a source of fever of unknown origin [41]. However, false positive exams can occur at sites of acute fracture, in normal healing bone up to 4 months after surgery, and in inflammatory arthritis [10]. Mild FDG accumulation is also seen within the normal bone marrow [10].

Chronic osteomyelitis is typically the result of inadequately treated acute osteomyelitis or it may follow exogenous bacterial contamination related to trauma or surgery [15]. It is characterized by the presence of lymphocytic and plasma cell infiltrates [15]. FDG PET imaging has been shown to have very good accuracy for the evaluation of chronic osteomyelitis [15].

Diabetic Foot:

FDG PET imaging can be used for the diagnosis of diabetic foot infections [8]. In diabetic patients, FDG might be at a disadvantage for evaluation of infection, however, the effect of hyperglycemia on FDG uptake at sites of infection and inflammation is not well documented [8,21]. In at least one study, elevated glucose levels did not seem to affect detection of sites of infection [8].

FDG PET can be positive in 81 to 93% of diabetic foot infections, with a specificity of 91% [8,21]. In a meta-analysis FDG PET/CT had a reported sensitivity of 74% and a specificity of 91% in diagnosing osteomyelitis in diabetic foot ulcers [49]. Unfortunately, lower sensitivity (43%), specificity (67%), and accuracy (54-62%) have also been reported [23].

Charcot joint typically demonstrates a low degree of of diffuse uptake [49]. SUVmax values can also  aid in differentiating neuropathic joint from infection [23]. In one study, the SUV max associated with osteomyelitis (4.38 +/- 1.39) was higher than that of neuropathic joint (1.3 +/- 0.4) [23].

Precise localization of the site of uptake can be difficult on conventional PET imaging [8]. The use of PET/CT imaging aids in the accurate localization of tracer uptake in order to differentiate between osteomyelitis and soft tissue infection [8].

Fever of unknown origin:

Fever of unknown origin is defined as recurrent fever of 38.3? C or higher, lasting 3 weeks or longer, and no diagnosis after appropriate inpatient or outpatient evaluation [15,28]. Some authors have proposed a subclassification including classic FUO in nonimmunecompromised patients, nosocomial FUO, neutropenic FUO, and FUO associated with HIV infection [15]. There are numerous causes for FUO with infection (the most common cause [28]) accounting for 13-43% of cases, and neoplasms for 15-25% [10,15,49]. Other causes include non-infectious inflammatory processes such as collagen vascular disease, vasculitis (up to 17% of cases of FUO [15]), granulomatous diseases, and drug reaction [10]. In between 10-40% of patients, the underlying disease may remain undiagnosed [15]. Tuberculosis is the most common infection that causes FUP in developing countries [28].

FDG accumulates at sites of infection and inflammation and FDG PET imaging has been shown to be more sensitive and more specific than Ga-67 scintigraphy for FUO evaluation [10,11,15]. Additionally- PET imaging can be performed in a much more rapid manner [10]. The reported sensitivity is between 81-100%, specificity between 81-90%, PPV of 81%, and an accuracy of 90% for identifying the source of the FUO [10,15]. The negative predictive value of a negative PET scan is also very (NPV up to 100%) high thereby excluding a focal pathologic etiology for the patients fever [18]. A meta-analysis comparing FDG PET/CT with gallium and leukocyte scintigraphy found FDG had the best performance with a summary sensitivity of 86%, specificity of 52%, and a diagnostic yield of 58% [49]. Overall, FDG PET can provide helpful information in identification of the source of the FUO in 25-69% of cases [10,15,18,49].

Infective endocarditis:

Infective endocarditis is an uncommon, but serious complication of valve replacement and has been reported in 0.3-6% of patients with valve prostheses [38,47]. The sensitivity of transthoracic echo for endocarditis ranges from 20-65% and for transesophageal echo from 70-90% [44].

Patient preparation is essential for proper exam interpretation [43]. At least 6 hours of fasting and 24 hours of a low carbohydrate and fat-allowed diet are recommended [43]. FDG PET imaging has been shown to have a sensitivity of 78-93%, a specificity of 71-90%, a PPV of 68%, a NPV of 94%, and an accuracy of 80% for prosthetic valve infection (compared to 64%, 100%, 100%, 81%, and 86%, respectively, for leukocyte scintigraphy) [38,45]. Drawbacks of FDG imaging for endocarditis include poor evaluation of the valve due to adjacent myocardial uptake and the inability of FDG PET imaging to distinguish between infection and inflammation [44].

False positive FDG exams can be seen in the first 1-2 months following surgery (likely related to inflammation or foreign body reactions) and this can affect the specificity and accuracy of the exam [38,43]- although a negative exam performed within three months of implantation has a high negative predictive value [47]. Other authors report that elevated uptake associated with non-infected prosthetic valves can be seen as late as 8 years following implantation [47]. Homogeneous uptake surrounding a prosthetic valve may be considered a normal variant, especially if it is mild in intensity [47]. Focal or intense uptake is more likely related to infection [47]. Generally, intense FDG uptake (prosthetic valve to background ratio > 4.4) is associated with a high probability of infection [38]. Other authors suggest an SUV max higher than 4 or a target to background ratio higher than 1.8 [44].

FDG PET is limited for the evaluation of native valve endocarditis [44]. This is likely due to the small size of the vegetation, lack of significant activated inflammatory cells, and continuous movement of the valve [44].

In patient's with infectious endocarditis, up to 44% of patients may have septic embolism and metastatic infection and whole body acquisitions should be performed to properly identify these sites [37,44]. Importantly, up to 50% of patients with septic embolism do not have any localizing signs or symptoms and it is not uncommon for there to be no clinical suspicion as well [37]. Reported sensitivity for metastatic infection is up to 100%, specificity up to 80-87%, PPV up to 89-90%, and NPV up to 100% [37]. One drawback of PET imaging in these patients is the lack of ability to clearly identify endocarditis due to background cardiac activity (sensitivity 39% in one study) [20,37].

In bacteremia/septic emboli:

S. aureus bacteremia is a severe infection associated with high morbidity and a 30 day mortality of 20% [46]. Patients with gram-positive bacteremia can develop infection at unsuspected sites (metastatic infection) in 16-68% of cases [20]. These metastatic foci of infection can be clinically silent (without localizing signs or symptoms) in up to one third of patients [20,46]. Risks factors for metastatic s. aureus infection include community acquired bacteremia, signs of infection for more than 48 hours prior to initiation of appropriate antibiotic treatment, fever for more than 72 hours following initiation of antibiotic therapy, and positive blood cultures more than 48 hours following initiation of appropriate antibiotic treatment [46]. Identification of these infectious foci is critical as prolonged antibiotic treatment is usually required [20]. Insufficiently eradicated infectious foci result in relapse infection in 12-16% of patients once antibiotics are discontinued [20].

The use of ¹⁸F-FDG PET/CT can aid in the detection of unsuspected sites of infection in these patients resulting in lower relapse rates and mortality [20,37]. In one study of patients with high risk bactermia, FDG PET identified metastatic foci of infection in 74% of patients (more than two-thirds of whom lacked signs or symptoms suggestive of metastatic complications) [46]. Treatment modification in these patients resulted in a significantly reduced 3 month mortality [46].

Patients on hemodialysis are also at higher risk for infection [39]. PET/CT can aid in identification of the sites of infection in up to 70% of patients [39]. The exam can also provide prognostic information as FDG positive patients have been shown to have a higher mortality (up to 26%) [39]. 

CNS infection:

FDG PET imaging can be used to aid in differentiating CNS toxoplasmosis infection from lymphoma in HIV patients [10]. CNS lymphoma typically demonstrates significantly greater FDG accummulation [10].

Spinal infection:

FDG PET imaging has proven to be very useful for the detection of disc space infection. Reported sensitivities of up to 100%, and specificities of up to 100% have been reported [2]. In general, increased FDG uptake is not seen in degenerative endplate abnormalities [2]. However, significant FDG uptake in degenerative spine disease occasionally occurs and foreign body reaction around uninfected spinal implants may also cause increased FDG uptake [42].

FDG-labeled leukocytes:

FDG-labeled leukocytes are also being studied for infection imaging. As with In-111 WBC's, the normal biodistribution of the tracer is to the reticuloendothelial system (bone marrow, liver, and spleen) [13]. Faint activity may be seen in FDG avid organs such as the brain and myocardium, but no significant renal or intestinal activity is seen [13]. Imaging can be performed 3-4 hours after injection, as opposed to the 24 hours required for In-111 WBC imaging [12,13]. Also- the tomographic nature of PET imaging enables more precise localization of sites of tracer accumulation [12]. The whole body and major organ dosimetry estimates from FDG-labeled WBC imaging are similar to those for In-111 WBC imaging [12]. The WBC labeling efficiency of FDG is lower than that of In-111 oxime (about 72% versus 90%) [12,15]. In vivo, about 25% of the activity is released from the leukocytes over 6 hours [15]. However, the overall sensitivity in one study higher than In-111 WBC's (87% versus 73%, but not statistically significant), while specificity, and accuracy were similar [12]. The accuracy was lowest for evaluation of osteomyelitis of the hands and feet [12]. False-positive exams can occur as a result of soft-tissue infection and physiologic accumulation of labeled leukocytes in granulating wounds [12]. Overall reported sensitivity is 86-87%, specificity 86%, PPV 92%, NPV 85%, and accuracy 86% [13].

PET Imaging in Inflammatory Conditions:

Sarcoid:

See also discussion in Chest section

The ACE level can be used to monitor disease activity in patients with sarcoid, however, it is elevated in only about 60% of patients with chronic sarcoid and can be unrelated to disease severity, progression, clinical course, and response to therapy [29]. Sarcoid is a mutlisystem inflammatory disease and FDG accumulation can be seen in active sarcoid lesions [14]. PET imaging offers more rapid clinical evaluation compared to traditional gallium imaging and is more accurate for the detection of extrapulmonary sites of diease [14]. In patients with chronic sarcoid, PET imaging can be used to detect sites of active inflammation and the findings on the PET exam can affect therapy decisions  in up to 81% of patients [29].

FDG PET can also be used to evaluate for the presence of cardiac sarcoid [30]. A limitation of FDG for the evaluation of cardiac sarcoid is the unpredictable physiologic cardiac tracer uptake even during fasting conditions that can interfere with detection of active disease [30]. Various methods have been proposed to decrease physiologic cardiac activity including prolonged fasting, preadministration of unfractioned heparin, and use of a high-fat low carbohydrate (HFLC) diet [30]. However, even when a HFLC diet is used, diffuse homogeneous cardiac uptake can still be seen in 3-7% of patients and focal uptake in the papillary muscles can be seen in 15-19% of patients [30].

For the diagnosis of cardiac sarcoid by FDG PET, in a metaanalysis the pooled sensitivity has been reported to be 89% (CI 79-96%) and specificity of 78% (CI 68-86%) [31]. The pooled prevalence of cardiac sarcoid in the studies was 50% which can obviously affect sensitivity and specificity [31]. In later stages that are characterized by fibrosis, FDG uptake may be low or not apparent [32].

The combined use of FDG PET and delayed enhanced cardiac MR may provide optimal detection of cardiac sarcoid by allowing differentiation of active granulomatous inflammation (MR-DE and FDG positive) from fibrous lesions (MR-DE positive and FDG negative) [30]. Correlation of the two exams can also help to definitively characterize areas of FDG uptake and avoid false positive exams associated with physiologic cardiac activity [30].

Vasculitis:

Patients with large vessel vasculitis typically have nonspecific constitutional symptoms of fever, malaise, weight loss, and an elevated ESR (small vessel vasculitis often results in hemorrhage and organ failure) [15,26]. Ultrasound can evaluate arteries in the proximal arm and axilla and can play a role in detection of giant cell arteritis (GCA) [21]. Sonographic findings include vessel wall edema (visible as hypoechoic circumferential wall thickening), vessel stenosis resulting in increased blood flow velocity and turbulence, and vascular occlusion [21]. On MRI, GCA demonstrates arterial wall thickening and abnormal gadolinium enhancement (sensitivity 81%, specificity 97%) [21].

PET imaging has been used to evaluate for large and medium-size vessel vasculitis in patients with Takayasu's and giant cell arteritis (generally for vessels that are larger than 4 mm in diameter) [11,15]. PET imaging is not reliable for the diagnosis of temporal artery inflammation [15]. ¹⁸F-FDG localization within inflammed vessels is strogly correlated with macrophage infiltration [22]. A characteristic feature of vasculitis on PET is a circumferential region of increased metabolic activity in the vessel wall [26].

FDG PET imaging is sensitive (77-92%) and highly specific (89-100%) in the diagnosis of large-vessel vasculitis in untreated patients with elevated inflammatory markers [15]. Reported NPV is 85%, and PPV is 100% [11]. PET imaging can also be used to monitor disease activity and response to treatment [15].  One hour post injection imaging appears adequate for the identification of vascular inflammation and delayed imaging does not appear to produce an additional advantage [19].

Atherosclerotic plaque:

FDG does not accumulate in normal vascular structures, but active atherosclerotic plaque can be identified on FDG PET imaging [25]. When FDG uptake is seen, it is most commonly in large vessels (over 1 cm in size) [26]. The presence of FDG uptake in the vessel wall is indicative of active plaque containing macrophages- focal  intense tracer uptake has been proposed to be a marker of lesions that are vulnerable to disruption (indicative of more inflammatory cellular components within the plaque) [26]. In fact, vascular FDG accumulation (such as in the carotid artiers and aorta) has been demonstrated to predict an increased incidence of future cardiovascular events [24,40].

¹⁸F-FDG uptake has been reported in coronary plaques, but localization is difficult due to the small caliber of the vessels, small size of the coronary plaques, coronary artery motion, and normal background uptake of FDG by the myocardium [27].

Uptake of FDG in abdominal aortic aneurysms has been reported to be associated with active inflammation which can result in weakening (due to release of the proteinaceous enzymes) of the wall that can precede rupture [34].

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