*2.2.1 Infective endocarditis*

Infective endocarditis (IE) is a life-threatening infection. In spite of advances in diagnosis and treatment, patients with IE still have high rates of morbidity and mortality. The diagnosis is based on modified Duke's criteria that classify patients into three categories: definite, possible, and rejected IE. The overall sensitivity of modified Duke's criteria is approximately 80% [28, 29].

18F-FDG is a useful adjunct for diagnosing IE with a pooled sensitivity and specificity of 61% and 88%, respectively (**Figure 6**). It is especially useful in the setting of prosthetic heart valves. False-negative results are associated with lesions below the limits of res olution of current systems and antibiotic treatment for more than 1 week prior to imaging. False positive results can occur with postoperative inflammation during the first 2 months after implantation and in the presence of severe prosthetic valve thrombosis [30, 31].

#### **Figure 5.**

*Asymptomatic knee arthroplasties. There is intense periprosthetic 18F-FDG around the right knee arthroplasty and to lesser extent around the left knee arthroplasty. The inability to be able to consistently discriminate between periprosthetic infection and aseptic inflammation, is a significant disadvantage of 18F-FDG.*

**Figure 6.**

*Infective endocarditis prosthetic aortic valve. 18F-FDG is especially useful for diagnosing infective endocarditis in patients with prosthetic heart valves.*

**Figure 7.**

*Infected left ventricular assist device and driveline. There is abnormal 18F-FDG accumulation around the device (top) and driveline (bottom, arrows).*

#### *2.2.2 Cardiac implantable electronic device infections*

CIEDs, such as permanent pacemakers, cardioverter-defibrillators, and cardiac resynchronization systems, have become increasingly important in the management of cardiac disease. The number of devices implanted has increased over time, especially in older patients with more comorbidities, leading to higher infection rates [32].

18F-FDG is useful for diagnosing CIED infections (**Figure 7**). Besides diagnosing pacemaker pocket infection, 18F-FDG delineates the extent of infection and improves the diagnostic accuracy of the modified Duke's criteria for CIED infection. It is useful for diagnosing left ventricular assist device infection, determining extent of infection, and monitoring treatment response [33–36]. In a meta-analysis of nearly five hundred patients, the pooled sensitivity of 18F-FDG PET/CT for diagnosing CIED infection was 83% and the pooled specificity was 89%. For diagnosing pocket infection, pooled sensitivity and specificity were 96% and 97%, respectively. The test was less sensitive for lead infection and CIED-IE with pooled sensitivity and specificity of 76% and 83%, respectively [37].

#### *2.2.3 Prosthetic vascular graft infections*

Although prosthetic vascular graft infections are infrequent, they are associated with high morbidity and sometimes, mortality. Underlying comorbidities increase risk of infection and infection-related complications, such as sepsis, enteric fistulae, spread of infection to other sites, and death [38].

18F-FDG accurately diagnoses prosthetic vascular graft infection, with sensitivity and specificity ranging from 88% to 100% [39, 40]. It is important to be cognizant of the fact that these grafts can incite a foreign-body inflammatory response that

### *PET Imaging of Infection DOI: http://dx.doi.org/10.5772/intechopen.110633*

can lead to increased 18F-FDG uptake in the absence of infection. Familiarity with typical 18F-FDG uptake patterns associated with infection and foreign body reaction is important. Vascular graft infection generally presents as focal or heterogeneously increased 18F-FDG uptake that projects over the vessel on the CT component of the examination (**Figure 8**). In contrast, the aseptic foreign body reaction presents as linear, diffuse, and homogeneous uptake along the graft (**Figure 9**) [41, 42].

### **2.3 Sarcoidosis**

Sarcoidosis is a multisystemic disease that most often affects the lungs and intrathoracic lymph nodes but can involve any organ in the body. The diagnosis is based on a combination of history, physical examination, radiologic and pathologic findings, and exclusion of other causes [43, 44].

18F-FDG, the molecular imaging study of choice for sarcoid, with an overall sensitivity of 89−100% is more sensitive than the ACE and soluble interleukin-2 receptor tests (**Figure 10**). Whole-body imaging facilitates identification of unsuspected disease sites and guides management in these patients [45, 46]. 18F-FDG is useful for monitoring treatment response. A decrease in 18F-FDG lesion avidity after the initiating treatment correlates with clinical improvement, while persistent activity identifies nonresponders [47, 48].

#### **Figure 8.**

*Infected aortic endovascular stent. There is intense heterogeneous 18F-FDG uptake surrounding the vascular stent.*

#### **Figure 9.**

*Uninfected endovascular stent. There is faint homogeneous 18F-FDG uptake around this stent (arrows). Compare this pattern with that of the infected stent in* **Figure 8***.*

#### **Figure 10.**

*Sarcoidosis. There is intense 18F-FDG uptake in multiple mediastinal lymph nodes, with patchy less intense uptake in both lungs, greater on the right.*

Pulmonary parenchymal uptake of 18F-FDG uptake correlates with active pulmonary disease and predicts response to anti-inflammatory treatment [49]. 18F-FDG uptake correlates with the bronchoalveolar lavage fluid neutrophil count and may serve as a noninvasive prognostic tool [50].

In patients with pulmonary involvement, distinguishing between fibrosis and fibrosis with active inflammation is important because patients with active inflammation could benefit from a change in therapy. Published data suggest that 18F-FDG can facilitate the differentiation between pure fibrosis and fibrosis plus inflammation because pulmonary fibrotic changes do not demonstrate uptake while active lesions do. It is superior to high-resolution CT and serological evaluation for this purpose [50, 51].

#### **2.4 Tuberculosis**

Tuberculosis is the leading cause of infectious disease–related mortality worldwide. One-fourth of the world's population is latently infected and 3–5% of these individuals develop active tuberculosis disease during their lifetime. The lungs are the most common site of involvement and pulmonary disease is present in more than 80% of cases. The most common sites of extrapulmonary disease are thoracic and cervical lymph nodes, spine, adrenal glands, meninges, and gastrointestinal and genitourinary tracts [52, 53]. Early, accurate diagnosis with prompt initiation of treatment is important to minimize morbidity and mortality and to reduce the likelihood of transmission. 18F-FDG is useful for identifying both pulmonary and extrapulmonary disease, measuring disease activity, identifying individuals with latent tuberculous infection at risk of developing an active infection, and monitoring response to treatment. In patients with active infection, there are two general patterns of 18F-FDG uptake. The lung pattern is associated with pulmonary tuberculosis. Mediastinal lymph nodes can be slightly enlarged and demonstrate moderate 18F-FDG uptake. The lymphatic pattern is associated with predominantly systemic, extra-thoracic disease. Mediastinal lymph nodes are larger and have higher 18F-FDG uptake than those in patients with the lung pattern. Immunocompetent patients tend to develop the lung pattern, while immunocompromised patients are more likely to develop the lymphatic pattern [54].

Lesion activity as measured by SUV correlates with disease activity. Using dual time-point imaging, it may be possible to distinguish active from inactive pulmonary tuberculomas. Active pulmonary tuberculomas have a higher SUV max at 1 and 2 hours and a greater increase in SUV max from early to late imaging compared to inactive tuberculomas [55]. 18F-FDG uptake can be present in clinically cured patients who do not go on to develop active disease. This may represent a post-treatment equilibrium in which the immune system prevents replicating bacilli from progressing to overt disease [56].

Identifying individuals with latent tuberculosis infection who are at risk of progressing to active infection is important because they should be treated. In one investigation, 18F-FDG showed infiltrates and/or fibrotic scars or active nodules in ten asymptomatic subjects with an initial negative screen for active disease. These subjects were significantly more likely to have 18F-FDG uptake within mediastinal lymph nodes compared to 25 subjects with either normal lung parenchyma or discrete small nodules [57].

18F-FDG can assess early treatment response when radiological features may remain unchanged, with consequent significant impact on patient management. In 28 subjects with multidrug-resistant disease, 18F-FDG-PET/CT performed 2 months into treatment was the best method for early prediction of treatment results and long-term outcomes [58].

In summary, 18F-FDG is valuable for staging tuberculosis, locating extrapulmonary disease, identifying patients with subclinical tuberculosis, and assessing early treatment response.

## **2.5 Fever of unknown origin**

Fever, or pyrexia, of unknown origin (FUO) is a fever that exceeds 38.3°C (101°F) on several occasions, with more than 3 weeks' duration of illness, and a failure to obtain a diagnosis after an appropriate inpatient or outpatient workup. FUO is divided into four categories: classic (the most common), nosocomial, neutropenic, and HIV-associated. Causes of classic FUO are divided into five categories: infection, neoplasm, inflammation, miscellaneous, and undiagnosed. The relative frequencies of these categories vary with the historical period, geographic region, care setting (tertiary versus community), and patient population. The etiology of FUO is undiagnosed in up to 50% of patients [59].

The workup of a patient with FUO consists of several first-line investigations: history and physical examination, laboratory tests, chest x-ray, and echocardiography when endocarditis is suspected. When first-line investigations do not yield a diagnosis, second-line procedures, including CT, MRI, and molecular imaging studies, are performed. 67Ga and labeled leukocyte scintigraphy, at one time the mainstays of molecular imaging for FUO, have been replaced by 18F-FDG as the molecular imaging test of choice in this population (**Figure 11**). Abnormalities identified with 18F-FDG guide additional investigations that may yield a final diagnosis. A negative study excludes these conditions with a reasonable certainty, thereby avoiding unnecessary additional testing. A negative result is a good predictor of a favorable prognosis. Performed within the first 1−2 weeks in the FUO workup, 18F-FDG is cost-effective by obtaining a diagnosis sooner, reducing the number of expensive, potentially invasive, diagnostic procedures performed, and decreasing the number of patients without a final diagnosis [59].

18F-FDG contributes useful information in children with FUO. In one investigation, 19 (43%) of 44 scans were helpful by allowing focused evaluation in 9 cases and eliminating further workup in 10 cases [60]. In one of the largest pediatric studies to date, (*n* = 110) 18F-FDG PET/CT established a definite diagnosis in 62% and led to treatment modification in 53% [61]. 18F-FDG is helpful in children with terminal chronic liver failure and FUO during the pretransplantation period, as well as in immunocompromised children with fever [62, 63].

#### **Figure 11.**

*Vasculitis. There is diffuse 18F-FDG throughout the wall of the thoracic and abdominal aorta with extension into the subclavian and iliac arteries. 18F-FDG is very sensitive for detecting large vessel vasculitis, which is a wellrecognized cause of fever of unknown origin.*

### **3. Gallium-68 citrate**

For nearly 50 years, 67Ga has been used for imaging infection. Now that gallium-68 citrate (68Ga) is available, investigators have studied the role of this agent in diagnosing infection [64]. In a pilot study, 68Ga accumulated in pulmonary and extra-pulmonary sites of disease in patients with tuberculosis was superior to CT for detecting extra-pulmonary disease. Not all pulmonary lesions concentrated 68Ga and the authors hypothesized that this radiopharmaceutical might be useful for differentiating active from inactive disease and for monitoring treatment response [65]. In another investigation of patients with tuberculosis, although more lesions overall were detected with 18F-FDG, brain lesions were better defined with 68Ga, presumably due to the lack of physiological brain uptake of this radiopharmaceutical [66].

The potential of 68Ga for diagnosing musculoskeletal infection also has been studied. In one investigation of 31 patients with suspected musculoskeletal infection, all 23 infections were detected. There were four false positive results all of which were due to tumor. Sensitivity, specificity, and accuracy were 100%, 76%, and 90%, respectively [67]. In a prospective investigation, 34 patients with clinically proven or suspected lower extremity PJI underwent 18F-FDG and 68Ga-citrate PET/CT. Sensitivity, specificity, and accuracy of 68Ga-citrate PET/CT and 18F-FDG PET/CT were 92%, 88%, and 91% and 100%, 38%, and 85%, respectively. The authors concluded that preliminary evidence suggests that 68Ga-citrate PET/CT potentially could be complementary to 18F-FDG PET/CT by facilitating the differentiation between infection and aseptic inflammation [68].

### **4. Labeled leukocytes**

Although 18F-FDG and 68Ga are useful in the diagnostic workup of patients with infectious diseases, they are not specific and accumulate in noninfectious conditions, including benign and malignant neoplasms, and various noninfectious inflammatory conditions. Considerable effort has been devoted to developing positron-emitting radiopharmaceuticals that are specific, or at least more specific for infection, than 18F-FDG and 68Ga.
