Nuclear Medicine Imaging of Fever of Unknown Origin

Abstract

Fever of unknown origin (FUO) is a prolonged febrile status without a known etiology despite accurate evaluation and diagnostic testing. It can be due to infection (21–54%), malignancies (6–31%), and/or inflammatory diseases (13–24%). Infection can be diagnosed in about 69.2% of the cases by noninvasive methods. Radiological imaging modalities (US, CT, and MRI) are often the first diagnostic imaging in the workup of patients with FUO. However, in order to identify the site of infection as the cause of FUO, it is often necessary to use nuclear medicine imaging, such as ⁶⁷Ga-citrate scintigraphy, labeled autologous leukocyte (WBC) scintigraphy, or [¹⁸F]FDG PET/CT. The ⁶⁷Ga-citrate scan shows quite low sensitivity (67%) and specificity (78%) for infectious diagnosis of FUO. Labeled WBC scintigraphy has higher sensitivity (60–85% and 96% for ¹¹¹In-oxine-WBC and for ^99mTc-HMPAO-WBC, respectively) and specificity (78–94% for ¹¹¹In-oxine-WBC and 92% for ^99mTc-HMPAO-WBC, respectively). By mirroring glucose metabolism, [¹⁸F]FDG accumulates equally well into inflammatory and neoplastic cells; this feature constitutes the pathophysiologic basis to perform [¹⁸F]FDG PET/CT in patients with FUO. The main advantages of [¹⁸F]FDG PET/CT are the high-quality imaging, short time consuming, and high diagnostic accuracy, especially in the spine and in chronic low-grade infections. Because of its high negative-predictive value, [¹⁸F]FDG PET/CT is considered the diagnostic procedure of choice for patients with FUO with low or intermediate probability of infection. Labeled WBC scintigraphy is instead the diagnostic procedure of choice in patients with FUO with high probability of infectious origin.

Appendices

Imaging in Patients with Fever of Unknown Origin

Fig. 10.1

[¹⁸F]FDG PET/CT in a patient with FUO: the coronal sections (CT, left; PET, middle; fused PET/CT, right) show increased [¹⁸F]FDG uptake in the right cervical, axillary, and mediastinal lymph nodes. The spleen is markedly increased in size. Lymph node biopsy demonstrated that a lymphoma was responsible for fever

Fig. 10.2

[ ¹⁸F]FDG PET/CT in a patient with FUO: the transaxial sections (CT, upper left; PET, upper right; fused PET/CT, lower left; MIP, lower right) show increased [¹⁸F]FDG uptake in the head of pancreas head. Final diagnosis was acute pancreatitis

Fig. 10.3

[ ¹⁸F]FDG PET/C in a patient with FUO: (a) the coronal sections (CT, left; PET, middle; fused PET/CT, right) show diffuse, markedly increased [¹⁸F]FDG uptake in the spleen and liver that are also enlarged in size (especially the spleen). (b) The transaxial midthoracic sections (CT, left; PET, middle; fused PET/CT, right) show irregularly increased [¹⁸F]FDG uptake in the right lung, where the low-dose CT image demonstrates the presence of cavitations, as well as broncho-hilar and centrolobular opacities; enlarged lymph nodes are also present both above and below the diaphragm. Final diagnosis was diffuse tubercular infection

Fig. 10.4

[¹⁸F]FDG PET/CT in a patient with FUO: (a) the sagittal sections (CT, left; PET, middle; fused PET/CT, right) show increased [¹⁸F]FDG uptake in the wall of thoracic aorta. (b) The coronal sections (CT, left; PET, middle; fused PET/CT, right) show increased [¹⁸F]FDG uptake, greater than liver uptake, in the epiaortic vessels and bilateral succlavia. Final diagnosis was acute Takayasu vasculitis

Fig. 10.5

[¹⁸F]FDG PET/CT in a patient with FUO who had been submitted to surgery of the lumbar spine with implantation of metallic hardware: (a) the sagittal sections (from left to right: CT; PET; fused PET/CT; MIP) and the transaxial sections (b) (CT, upper left; PET, upper right; fused PET/CT, lower left; MIP image, lower right) show increased [¹⁸F]FDG uptake in posterior tissues near to the vertebral implant. This post-surgical infection was responsible for fever

Fig. 10.6

^99mTc-HMPAO-WBC scintigraphy in a patient with FUO: the planar anterior and posterior views at 2 h (upper panel) and 24 (bottom panel) clearly show an area of reduced accumulation of labeled leukocytes in the lumbar vertebral region (L3–L5). MRI confirmed the presence of spine infection, as suspected on the basis of the scintigraphic pattern, as the cause of fever

Fig. 10.7

[¹⁸F]FDG PET/CT in a patient with FUO: (a) the coronal slices (CT, left; PET, middle; fused PET/CT, right) show markedly increased [¹⁸F]FDG uptake in the mid-portion of right lung. (b) The transaxial sections (CT, left; PET, middle; fused PET/CT, right) localize such area of focally increased tracer uptake in the posterior region of right lung. The low-dose CT images show diffuse ground-glass opacities corresponding to the areas of increased [¹⁸F]FDG uptake. Fever was due to bacterial pneumonia

Fig. 10.8

[¹⁸F]FDG PET/CT in a patient with FUO: (a) the transaxial sections (CT, left; PET, middle; fused PET/CT, right) show increased [¹⁸F]FDG uptake at the left sacroiliac joint, with involvement also of the adjacent iliopsoas muscle. (b) and (c): Two coronal sections in different planes visualize extension of the infection along the whole anterior portion of the iliopsoas muscle. (d) Sagittal sections better visualize markedly increased [¹⁸F]FDG uptake involving simultaneously the left sacroiliac joint and the left iliopsoas muscle. Final diagnosis was fever caused by infection of the left sacroiliac joint with soft tissue involvement

Fig. 10.9

[¹⁸F]FDG PET/CT in a patient with FUO: the tomographic images (shown in (a, coronal), (b, sagittal), and (c, transaxial)) shows a well-defined focus of markedly increased [¹⁸F]FDG uptake located between the quadriceps and the sartorius muscles, with a central area with reduced/absent uptake; there is no involvement of the femoral bone (CT, left; PET, middle; fused PET/CT, right). The low-dose CT images confirm the presence of a mass with mildly reduced and inhomogeneous density. Histology of a biopsy sample from the mass revealed the presence of sarcoma

Fig. 10.10

[¹⁸F]FDG PET/CT in a patient with FUO who had been submitted to implantation of a cardiac pacemaker. Increased [¹⁸F]FDG uptake was observed in the subcutaneous pacemaker task and around the initial portion of the lead (transaxial CT, upper left; PET, upper right; fused PET/CT, lower left; MIP image, lower right). These findings indicate infection of the pacemaker task as the cause of fever

Fig. 10.11

[¹⁸F]FDG PET/CT in a patient with FUO who had been submitted to implantation of a prosthetic aortic valve. Increased [¹⁸F]FDG uptake was observed at the prosthetic aortic valve, well identified by the metallic artifact in the low-dose CT component of the scan (transaxial CT, upper left; PET, upper right; fused PET/CT, lower left; MIP image, lower right). These findings indicate infective endocarditis as the cause of fever

Fig. 10.12

[¹⁸F]FDG PET/CT in a patient with FUO: (a) the coronal sections (CT, left; PET, middle; fused PET/CT, right) show markedly increased [¹⁸F]FDG uptake involving at many mediastinal lymph nodes that appear as bilateral peri-hilar consolidations. In addition, transaxial sections of the lower limbs (b) show increased tracer uptake at multiple subcutaneous nodules. Flare of sarcoidosis was responsible for fever

Fig. 10.13

[¹⁸F]FDG PET/CT in a patient with FUO: the sagittal sections (CT, left; PET, middle; fused PET/CT, right) show moderately increased [¹⁸F]FDG uptake at the nasopharynx, suggesting acute nasopharyngitis. These PET/CT findings turned out to be false positive, since acute nasopharyngitis was not present; the moderately increased [ ¹⁸F]FDG uptake was probably due to a nonspecific inflammatory condition

Fig. 10.14

[¹⁸F]FDG PET/CT in a patient with FUO: coronal sections (from left to right: CT, PET, fused PET/CT, MIP image) showing markedly increased [¹⁸F]FDG uptake in the bone marrow. Final diagnosis was myelodysplasia as the cause of fever

Clinical Cases

10.1.1 Case 10.1

• Elena Lazzeri 

10.1.1.1 Background

A 65-year-old man with fever, pain in the epigastric region, and jaundice. The CT scan of the abdomen showed a rather diffuse enlargement in size of the pancreas, without clear signs of focal lesion(s) (Fig. 10.15a). MRI confirmed the increase of pancreas size, but also visualized a focal lesion (about 3 cm in size) in the head of pancreas (Fig. 10.15b).

Fig. 10.15

(a) Abdominal CT showing diffuse enlargement of pancreas, with a somewhat inhomogeneous parenchyma. (b) Abdominal MRI showing the increase of contrast enhancement of the head and body of pancreas. (c) Transaxial sections of [¹⁸F]FDG PET/CT (CT, upper left; PET, upper right; fused PET/CT, lower left; MIP image, lower right), showing diffuse, mildly increased tracer uptake in the whole pancreas. These findings are consistent with pancreatitis

Based on these findings, the patient was referred for [¹⁸F]FDG PET/CT for suspected pancreatic cancer. Contrary to expectation, the [¹⁸F]FDG PET/CT scan only showed diffuse, mildly increased uptake of the pancreas parenchyma (Fig. 10.15c). Based on this pattern, the hypothesis of pancreatic cancer was ruled out, as the findings were consistent with pancreatitis. The final diagnosis was autoimmune pancreatitis.

10.1.1.2 Suspected Site of Disease

Pancreas.

10.1.1.3 Radiopharmaceutical Activity

[¹⁸F]FDG, 270 MBq.

10.1.1.4 Imaging

[¹⁸F]FDG PET/CT acquired 60 min post injection, including CT scout view (120 kV, 10 mA), whole-body CT scan (140 kV, 80 mA), and PET (3 min/FOV). Images were reconstructed with and without attenuation correction using the low-dose transmission CT scan.

10.1.1.5 Conclusion/Teaching Point

[¹⁸F]FDG PET/CT ruled out the presence of neoplastic disease of pancreas and identified the origin of FUO and jaundice as autoimmune pancreatitis.

10.1.2 Case 10.2

• Viviana Frantellizzi 

(Nuclear Medicine Department, University “La Sapienza”, Rome, Italy

).

10.1.2.1 Background

A 31-year-old woman with autosomic dominant hyper-IgE syndrome (a rare form of congenital, non-X-linked severe immune deficiency) was referred for remittent FUO. Medical history included right nephrectomy at the age of 8 years because of abscess, as well as abdominal abscesses at multiple sites and recurrent bronchopneumonia; the patient was kept on chronic antibiotic therapy.

MRI of the upper (coronal T2-STIR images in Fig. 10.16a) showed multiple focal roundish lesions in the liver parenchyma with regular wall and inhomogeneous fluid content; numerous foci of lung parenchymal consolidation and bronchiectasis on the basal region of the right lung were also detected. These findings were consistent with the clinical suspicion of multiple abscess localizations.

Fig. 10.16

(a) Coronal MR images in two different planes showing focal lesions in the upper portion of liver, associated with “honeycomb-type” changes in the anterior and basal regions of right lung; both changes are consistent with infection. (b) ^99mTc-HMPAO-WBC scintigraphy (anterior and posterior planar whole-body views acquired at 3 h and 24 h) showing abnormal accumulation of labeled leukocytes at the base of right lung and upper liver, increasing over time and matching the MRI findings. The overall imaging results indicated the presence of multiple abscesses in right lung and liver

^99mTc-HMPAO-WBC scintigraphy was performed to better characterize the focal lesions detected on MRI. The scan showed mild but increasing over time accumulation of labeled leukocytes in the antero-basal region of the right lung and in the upper region of the liver (Fig. 10.16b), matching the MRI findings and confirming the diagnosis of multiple abscess localizations in the liver and in the lower lobe of right lung.

10.1.2.2 Suspected Site of Infection

Lung and liver.

10.1.2.3 Radiopharmaceutical Activity

^99mTc-HMPAO-WBC scintigraphy: acquisition of planar imaging at 1 h, 4 h, and 20 h.

10.1.2.4 Conclusion/Teaching Point

^99mTc-HMPAO-WBC scintigraphy detected multiple sites of labeled leukocyte accumulation matching the MRI findings, therefore confirming the diagnosis of multiple abscess localizations in the liver and in the lower lobe of right lung.

10.1.3 Case 10.3

• Elena Lazzeri 

10.1.3.1 Background

A 56-year-old man with prior diagnosis of lung infection (but without certain etiology), undergoing long-lasting antibiotic treatment. Fever and coughing persisted despite antimicrobial therapy; moreover, lumbar back pain appeared.

The patient was referred for [¹⁸F]FDG PET/CT to evaluate the presence and extension of lung infection. The PET/CT scan showed diffuse, increased [¹⁸F]FDG uptake in pulmonary parenchyma, bilaterally (Fig. 10.17). PET images showed, furthermore, increased [¹⁸F]FDG uptake in the lumbar spine, corresponding to L4–L5. The findings were consistent with the persistence of lung infection and appearance of infection in the lumbar spine. A subsequent MRI scan confirmed lumbar L4–L5 spondylodiscitis. Change in the antibiotic treatment plan resulted in rapid improvement of the patient’s clinical conditions.

Fig. 10.17

[¹⁸F]FDG PET/CT: the transaxial sections (CT, upper left; PET, upper right; fused PET/CT, lower left; MIP image, lower right) show markedly increased [¹⁸F]FDG uptake in both lungs (upper and middle lobes of right lung, upper lobe of left lung) associated with irregularly shaped consolidation areas detected in the low dose CT scan. Increased [¹⁸F]FDG uptake was also noted in the lumbar spine (see MIP image; tomographic images not shown here). These findings, obtained after prolonged antibiotic therapy, classified the patient as “no responder” to the antibiotic regimen employed and led to change the antimicrobial agent

10.1.3.2 Suspected Site of Infection

Lungs.

10.1.3.3 Radiopharmaceutical Activity

[¹⁸F]FDG, 184 MBq.

10.1.3.4 Imaging

[¹⁸F]FDG PET/CT acquired 60 min post injection, including CT scout view (120 kV, 10 mA), whole-body CT scan (140 kV, 80 mA), and PET (3 min/FOV). Images were reconstructed with and without attenuation correction using the low-dose transmission CT scan.

10.1.3.5 Conclusion/Teaching Point

The [¹⁸F]FDG PET/CT findings confirmed the persistence of pulmonary infection with appearance of septic embolism in the spine. Based on these findings, the patient was classified as “non-responder” to antibiotic treatment; subsequent change of the antimicrobial agent resulted in improved clinical status.