Infection and Inflammation
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Solve questions (24) →Contents
- 24.1 Ga-67 Scintigraphy
- 24.2 Labelled Leucocyte Scintigraphy (In-111 Oxine, Tc-99m HMPAO)
- 24.3 Infection/Inflammation Imaging with FDG PET/CT
- 24.4 Investigation of Fever of Unknown Origin (FUO)
- 24.5 Assessment of Osteomyelitis
- 24.6 Assessment of Prosthesis/Graft Infection
- 24.7 Infective Endocarditis and Vascular Graft Infection
- 24.8 Sarcoidosis and Granulomatous Diseases
- Key Points for the Board
- Current guidelines on this chapter's topics
Learning objectives and modules3 modules · about 2 h 40 min
Learning objectives
After this chapter you will be able to:
- Explain the uptake mechanisms, normal distribution and indications of Ga-67.
- Compare labelled leukocyte scintigraphy with In-111 oxine and Tc-99m HMPAO in terms of technique, distribution and indications.
- Explain the role of FDG PET/CT in infection and inflammation and its use in fever of unknown origin (FUO).
- Select the appropriate imaging algorithm in osteomyelitis and in prosthetic and graft infection.
- Interpret imaging findings and patient preparation in infective endocarditis, vasculitis and sarcoidosis.
Modules
The chapter is divided into study modules without changing the order of the text: read, watch the animations, then answer the questions linked to those headings.
- Module 124.1–24.2 Ga-67 Scintigraphy · Labelled Leucocyte Scintigraphy (In-111 Oxine, Tc-99m HMPAO)1 h 15 min · 4 animations · 26 questionsAnswer the questions →
- Module 224.3–24.6 Infection/Inflammation Imaging with FDG PET/CT · Investigation of Fever of Unknown Origin (FUO) · Assessment of Osteomyelitis · Assessment of Prosthesis/Graft Infection50 min · 23 questionsAnswer the questions →
- Module 324.7–24.8 Infective Endocarditis and Vascular Graft Infection · Sarcoidosis and Granulomatous Diseases · Key Points for the Board35 min · 13 questionsAnswer the questions →
Times are estimates: 130 words per minute, 3 min per animation, 1.5 min per question.
MOST FREQUENTLY ASKED IN THIS CHAPTER
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Uptake mechanism: multiple → transferrin, lactoferrin, siderophores (bacteria-specific), leucocyte uptake
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Half-life: 78.3 hours, gamma energies: 93, 185, 300, 394 keV
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Imaging: 48-72 hours after injection, medium-energy collimator
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Normal biodistribution: liver > spleen > bone marrow + kidney (early) + bowel (late)
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Sarcoidosis patterns: Panda (parotid + lacrimal) + Lambda (bilateral hilar + right paratracheal) → together highly specific
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Today replaced by FDG PET/CT for many indications
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In-111 oxine: NO kidney/bladder uptake, NO bowel uptake (up to 24 hours) → preferred for abdominal infection
24.1 Ga-67 Scintigraphy8 questions
Ga-67 Citrate – Basic Properties
Physical Properties:
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Radionuclide: Ga-67 (gallium-67)
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Half-life: 78.3 hours (~3.26 days)
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Decay: electron capture (EC)
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Gamma energies: 93 keV, 185 keV, 300 keV, 394 keV (multiple photopeaks)
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Fe³⁺ analogue: because it cannot be reduced to the +2 state in the body, it does not enter haem and the cytochrome system and is retained in the cell without reduction; it decays to stable Zn-67
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Cyclotron production
Uptake Mechanism:
Uptake of Ga-67 in infected and tumour tissue occurs by multiple mechanisms:
1. Transferrin binding: Ga-67 binds to transferrin in plasma → increased vascular permeability at the site of infection/inflammation → the transferrin-Ga-67 complex passes into the extravascular space
2. Lactoferrin binding: neutrophils and macrophages secrete lactoferrin → Ga-67 binds to lactoferrin with high affinity
3. Siderophore binding: bacteria produce siderophores (iron-binding molecules) → Ga-67 binds to siderophores → direct bacterial uptake
4. Leucocyte uptake: taken up directly by activated leucocytes 5. Tumour uptake: uptake in tumour cells with increased transferrin receptor expression
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Lactoferrin is also present in the lacrimal and salivary glands and in the lactating breast; this explains physiological Ga-67 uptake in these glands. The affinity of lactoferrin for gallium is higher than that of transferrin; gallium does not bind to red cells
BOARD TIP
▸
"If asked about the mechanism of Ga-67 uptake at a site of infection?"
→ Multiple mechanisms: transferrin (vascular permeability), lactoferrin (neutrophil/macrophage), siderophore (bacterial), direct leucocyte uptake.
▸
"Why is Ga-67 taken up by both infection and tumour?"
→ The transferrin receptor is expressed both on activated leucocytes and on tumour cells → not specific.
Left: capillary lumen and extravascular space. Ga-67 circulates on transferrin and leaves the vessel through widened endothelial gaps; at the focus it moves to lactoferrin released by neutrophils, binds a siderophore and is taken into bacteria, and is held by activated leukocytes; in tumour it binds the transferrin receptor, is endocytosed and released from transferrin in the endosome. Right: legend and sequence of events.
Continuous stream · no seeking
Ga-67 travels on transferrin; it accumulates at a focus through increased permeability, lactoferrin, siderophores and leukocytes, and enters tumour cells through the transferrin receptor cycle.
Source: uptake mechanisms from the book (24.1); transferrin cycle and lactoferrin granules from OpenStax A&P 2e §18.3; Tsan, J Nucl Med 1985; Weiner, Nucl Med Biol 1996; capillary structure from OpenStax §20.1. Timing is representative.
How to use: a single click on the drawing pauses and resumes; in the first step ↑ ↓ or the buttons below switch between normal tissue and infection; ← → change steps.
Did this animation help you understand the topic?
Figure 24.1: Mechanisms of Ga-67 citrate uptake at a focus of infection/inflammation and in tumour (schematic).
Normal Biodistribution
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Liver: most intense uptake (transferrin metabolism)
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Spleen: marked uptake
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Bone marrow: diffuse uptake
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Kidneys: marked in the first 24 hours (renal excretion) → decreases by 48-72 hours
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Bowel: from 24 hours onwards increasing uptake (hepatobiliary and colonic excretion)
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Excretion: 15-25% of the dose is excreted in the urine in the first 24 hours, thereafter mostly via the colon; the critical organ is the colon. The biological half-life is longer than the physical half-life (only ~1/3 of the dose is excreted in 4 weeks)
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Salivary glands, lacrimal glands, nasal mucosa: mild uptake
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Breast tissue: marked uptake during lactation
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Thymus: normal uptake in children and young adults (rebound hyperplasia after chemotherapy → intense uptake)
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Marked renal uptake after 24 hours is pathological. With transferrin saturation (iron overload, recent transfusion, chemotherapy) or liver failure, liver uptake falls and renal and bone activity increase
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Bilateral, diffuse, intense renal uptake at 48-72 hours suggests acute (drug-induced) interstitial nephritis, pyelonephritis or vasculitis; marked uptake is not expected in ATN (differentiation of AIN from ATN). Deferoxamine chelates Ga-67 and increases its renal excretion
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Benign uptake pitfalls: recent surgical wound (1-2 weeks), IM injection sites, increased salivary gland uptake after head and neck RT
Protocol
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Dose: 185-370 MBq (5-10 mCi) IV
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Imaging time:
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Infection: 48-72 hours after injection (optimal)
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Tumour (lymphoma): 48-72 hours after injection
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Early images (24 hours): intense renal activity → abdominal assessment difficult
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Collimator: medium-energy collimator
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Energy windows: multiple photopeaks (93, 185, 300 keV → all three used together)
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Whole-body scan + regional SPECT/CT
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Colonic activity: bowel activity that moves on serial delayed images (± SPECT/CT) is distinguished from a fixed pathological focus; a mild laxative or enema is given if needed
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Preparation and information to obtain (SNM 3.0, 2004): unless the patient is too ill or cannot eat solid food, bowel preparation with oral laxatives and/or enemas before imaging is recommended; residual bowel activity is the most common cause of both false positive and false negative findings. Recent haemolysis or transfusion (transferrin saturation), gadolinium for MRI within 24 hours, chemotherapy and radiotherapy, desferrioxamine therapy, and recent surgery or trauma alter Ga-67 distribution and are asked about. The 93 keV window is not used within 24-36 hours of a Tc-99m study
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Other pitfalls: low-grade hilar nodal uptake can be a normal variant in adult smokers; thymic uptake under 2 years of age and in children after chemotherapy; healing fractures, old pin sites and loose prostheses complicate interpretation for osteomyelitis
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In peritonitis Ga-67 (or labelled leucocytes) shows diffuse, sheet-like activity in the abdomen and pelvis; activity collects in the paracolic gutters and along the lateral and subdiaphragmatic surfaces of the liver
Clinical Indications
Infection:
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Chronic osteomyelitis (especially spinal)
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Lung infections (Pneumocystis jirovecii → PCP)
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PCP: diffuse intense uptake in both lungs is seen even with a normal chest radiograph (without hilar node or parotid uptake). In immunosuppressed patients Kaposi sarcoma is Ga-67-negative and Tl-201-positive; lymphoma and mycobacterial infection are Ga-67-positive
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Diffuse lung Ga-67 uptake with a normal chest radiograph: PCP, CMV pneumonia, drug toxicity (bleomycin, amiodarone), sarcoidosis, lymphocytic interstitial pneumonia
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Ga-67 in AIDS: eye, adrenal, renal and colonic uptake (± diffuse lung uptake; also in transplant patients) suggests CMV; salivary gland and diffuse lung uptake suggests DILS or lymphocytic interstitial pneumonia (parotid enlargement, clubbing in children); lymph node uptake alone suggests lymphoma or MAI
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Tuberculosis
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Investigation of fever of unknown origin (FUO) → today largely replaced by FDG PET/CT
Inflammation:
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Sarcoidosis ("Lambda" and "Panda" patterns)
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Interstitial lung diseases
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Idiopathic pulmonary fibrosis
Oncology:
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Lymphoma (Hodgkin and non-Hodgkin) → today replaced by FDG PET/CT
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Hepatocellular carcinoma
Ga-67 Patterns in Sarcoidosis
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"Panda" sign: bilateral parotid and lacrimal gland uptake → panda appearance of the face
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"Lambda" (λ) sign: bilateral hilar + right paratracheal lymph node uptake → appearance of the letter lambda (λ)
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Panda + Lambda together → highly specific for sarcoidosis
BOARD TIP
▸
"What is the Panda sign on Ga-67 scintigraphy?"
→ Bilateral parotid + lacrimal gland uptake.
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"Lambda sign?"
→ Bilateral hilar + right paratracheal lymph node uptake.
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"Both together?"
→ Highly specific for sarcoidosis. FDG PET/CT is preferred today for assessing sarcoidosis.
Figure 24.2: The "Panda" and "Lambda" (λ) signs characteristic of sarcoidosis on Ga-67 scintigraphy (schematic).
Did this figure help you understand the topic?
Advantages and Disadvantages of Ga-67
Advantages:
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Whole-body scanning possible
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Effective in chronic infections (where leucocyte infiltration is scant)
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Superior to labelled leucocytes in spinal osteomyelitis
Disadvantages:
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Long waiting time (48-72 hours)
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High radiation dose (effective dose ~10-18 mSv)
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Low spatial resolution
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Bowel activity → makes abdominal assessment difficult
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Cannot distinguish infection from tumour (non-specific)
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Today replaced by FDG PET/CT for many indications
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Report content (SNM 3.0, 2004): in addition to the common items (see 27), activity, imaging times after injection, type of images (whole body, regional, SPECT/CT) and bowel preparation. Findings: sites of abnormal uptake, the degree of uptake relative to liver, bone or bone marrow and whether it increases on delayed images, and comparison of site and extent with other scintigraphy such as a bone scan if available; confounding factors (residual bowel activity, recent transfusion, chemotherapy). The impression is given as positive, negative or indeterminate, with its clinical significance and a differential diagnosis where appropriate
24.2 Labelled Leucocyte Scintigraphy (In-111 Oxine, Tc-99m HMPAO)18 questions
General Principles
Labelled leucocyte scintigraphy is based on labelling the patient's own leucocytes with a radioactive agent in vitro and reinjecting them. Labelled leucocytes migrate to the site of infection/inflammation by chemotaxis → focal uptake.
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Labelled leucocyte scintigraphy is regarded as the reference (gold-standard) scintigraphic method for infection imaging; uptake depends on active migration of leucocytes (chemotaxis) rather than vascular permeability
Basic Steps:
1. 40-60 mL of venous blood is taken from the patient 2. Leucocytes are separated by sedimentation (red cells are settled out) 3. Leucocytes are labelled with the radioactive agent 4. Labelled leucocytes are reinjected IV into the patient 5. Imaging is performed at the appropriate time
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Quality control before reinjection: labelling efficiency (ratio of cell-bound activity to total activity) is calculated; cell viability is assessed with the trypan blue exclusion test and clumping by microscopy
In-111 Oxine Labelled Leucocytes
Physical Properties of In-111:
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Half-life: 67.3 hours (~2.8 days)
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Gamma energies: 171 keV and 245 keV
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Decay: electron capture
Labelling Mechanism:
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Oxine (8-hydroxyquinoline) → lipophilic chelating agent
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The In-111 oxine complex crosses the cell membrane → oxine dissociates inside the cell → In-111 binds to cytoplasmic proteins
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Labelling with In-111 oxine is done in a plasma-free medium (transferrin binds In-111 and lowers efficiency); In-111 tropolone or mercaptopyridine-N-oxide allow labelling in plasma. With Tc-99m HMPAO labelling can be done in a small amount of plasma
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Labelling efficiency: 50-80% (EANM; typically 75-90% in textbooks); below the lower limit, cell viability is checked
Protocol:
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Dose: 10-18.5 MBq (0.3-0.5 mCi)
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Imaging: 18-24 hours after injection (optimal)
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Early images (4 hours): vascular phase → risk of false positive
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Delayed images (24 hours): leucocyte migration complete → more specific
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Critical organ: spleen (receives the highest organ dose with In-111-WBC)
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Medium-energy collimator
Normal Biodistribution:
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Liver: intense uptake
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Spleen: most intense uptake (damaged leucocytes are retained in the spleen)
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Bone marrow: diffuse uptake
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Lungs: transient uptake on early images (leucocyte margination) → disappears by 24 hours
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Marked lung activity on early images and increased liver activity or focal hot spots in the lung on delayed images suggest that leucocytes were damaged or clumped during labelling (technical error)
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NO kidney or bladder uptake → advantage for assessing renal/urinary infection
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Normally NO bowel uptake (up to 24 hours) → advantage for assessing abdominal infection
BOARD TIP
▸
"Is there normal bowel uptake on In-111 labelled leucocyte scintigraphy?"
→ NO (up to 24 hours). It is therefore advantageous for assessing abdominal infection.
▸
"Normal kidney/bladder uptake?"
→ NONE → advantage for assessing urinary infection. Comparison: Ga-67 HAS bowel and renal uptake → makes abdominal assessment difficult.
Tc-99m HMPAO Labelled Leucocytes
Tc-99m HMPAO (Hexamethylpropyleneamine Oxime / Exametazime):
Labelling Mechanism:
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Tc-99m HMPAO → lipophilic complex → crosses the cell membrane
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Converted to a hydrophilic form inside the cell → trapped in the cell
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Although mixed leucocytes are labelled, Tc-99m HMPAO is retained mainly in granulocytes; it is therefore suitable for acute neutrophilic infections
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Labelling efficiency: 40-80% (EANM; slightly lower than In-111 oxine); below the lower limit, cell viability is checked
Left: sedimentation and leukocyte labelling steps in a tube; early and late leukocyte images; labelled-leukocyte and sulphur-colloid images of a hip prosthesis. Right: trapping of In-111 oxine or Tc-99m HMPAO inside the cell with labelling efficiency, the L/R ratio over time and count profiles of both agents along the stem.
Continuous stream · no seeking
With labelled leukocytes infection shows uptake that rises on late images, and is told from marrow by discordance with colloid.
Source: labelling steps, efficiencies, EANM positivity criterion and dual isotope from the book (24.2). Images, L/R curves and count profiles are representative.
How to use: a single click on the drawing pauses and resumes; in the first step ↑ ↓ or the buttons below switch the agent (In-111 oxine / Tc-99m HMPAO); ← → change steps.
Did this animation help you understand the topic?
Figure 24.3: Steps of in vitro leucocyte labelling and the intracellular retention mechanisms of In-111 oxine and Tc-99m HMPAO (schematic).
Protocol:
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Dose: 185-370 MBq (5-10 mCi)
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Imaging: 1-4 hours after injection (early) and, if needed, at 24 hours (delayed)
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Low-energy high-resolution (LEHR) collimator
Normal Biodistribution:
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Liver, spleen, bone marrow (similar to In-111)
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Kidney and bladder: free pertechnetate and hydrophilic metabolites of Tc-99m HMPAO are excreted renally → kidney and bladder uptake PRESENT
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Bowel: hepatobiliary excretion → bowel uptake PRESENT (especially on delayed images)
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Gallbladder: uptake may occur
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IBD: early imaging with HMPAO-WBC (30 min and 2-3 hours) is needed because after ~3-4 hours physiological bowel activity becomes misleading. Skip uptake in the small bowel suggests Crohn disease, continuous colonic uptake starting from the rectum suggests ulcerative colitis
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In IBD with In-111-WBC, early (2-4 hours) images are acquired in addition to the 24-hour image, because leucocytes shed into the lumen are carried distally on delayed images; 4-day faecal In-111 excretion is a quantitative measure of disease activity
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Diffuse leucocyte uptake along the colon: pancolitis, pseudomembranous colitis (antibiotic-associated C. difficile), ischaemic colitis; swallowed leucocytes (sinusitis, pneumonia) also cause false positives in the bowel
BOARD TIP
▸
"Is bowel uptake normal with Tc-99m HMPAO labelled leucocytes?"
→ YES (because of hepatobiliary excretion, especially on delayed images). In-111 oxine is therefore preferred for assessing abdominal infection (no bowel uptake). However, the advantages of Tc-99m HMPAO are: better image quality (140 keV), SPECT possible, same-day result, lower radiation dose.
Figure 24.4: Normal biodistribution of Ga-67 citrate, In-111 oxine-WBC and Tc-99m HMPAO-WBC; differences in kidney, bladder and bowel activity (schematic).
Did this figure help you understand the topic?
In-111 Oxine vs Tc-99m HMPAO Comparison
| Feature | In-111 Oxine | Tc-99m HMPAO |
|---|---|---|
| Half-life | 67.3 hours | 6 hours |
| Gamma energy | 171, 245 keV | 140 keV |
| Labelling efficiency | 50-80% (EANM; typically 75-90%) | 40-80% (EANM) |
| Imaging time | 18-24 hours | 1-4 hours |
| Image quality | Moderate | Better (140 keV ideal) |
| SPECT | Limited | Excellent |
| Normal bowel uptake | None (up to 24 hours) | Present (hepatobiliary excretion) |
| Normal kidney/bladder | None | Present (renal excretion) |
| Abdominal infection | Preferred | Limited (bowel activity) |
| Radiation dose | High | Low |
| Same-day result | NO (wait 24 hours) | YES |
| Dual isotope (with Tc-99m) | YES (different energy) | NO (same isotope) |
| Bone marrow SPECT | YES (dual isotope) | NO |
EANM Recommendations (Labelled WBC):
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Tc-99m HMPAO (exametazime) labelled WBC is preferred for most indications; for assessing the kidney, bladder, gallbladder and bowel, In-111-WBC, which shows no excretion in these organs, is more suitable
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Activity: Tc-99m-WBC 185-370 MBq (2.0-4.1 mSv); In-111-WBC 10-18 MBq (3.6-6.5 mSv)
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Positivity criterion: increase in the intensity and/or size of uptake from early to delayed images; in doubtful cases, an increase in the lesion/reference (L/R) ratio on the delayed image
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Breastfeeding: no interruption needed after In-111-WBC; a 12-hour interruption after Tc-99m-WBC
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Preparation and pitfalls (EANM 2018): patients on antibiotics are not excluded a priori; data on their effect are conflicting (some authors recommend waiting 1-2 weeks after stopping treatment, or repeating a doubtful study 2 weeks later), and the decision is made case by case with the referring physician. Antibiotics and steroids may reduce leucocyte migration
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With Tc-99m HMPAO-WBC for abdominal infection and inflammatory bowel disease, images are acquired only at 30 minutes and 2-3 hours; later, the HMPAO metabolite excreted by the liver causes false positive bowel activity (4-6 hours, and if needed 20-24 hours, only for suspected fistula or abscess). Infection of abdominal aortic and iliac grafts is also imaged within 3 hours. In-111-WBC do not accumulate in normal bowel, so any bowel activity is abnormal
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Delayed images are acquired with time corrected for physical decay, and all images are displayed on the same absolute count scale; in semi-quantitative assessment an increase of the L/R ratio by at least 10% on late images favours infection
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False positives: non-segmental focal lung uptake on early images (labelling or reinjection fault; disappears by 4 hours), wounds healing by secondary intention (stomas such as tracheostomy, ileostomy, gastrostomy, skin grafts), vascular access and dialysis catheters, lumbar puncture sites. False negatives or low uptake: spondylodiscitis (oedema compressing capillaries), poor vascularity of the toes in diabetic foot, some chronic infections and abscesses, fungal infection
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Labelling must be done under strictly aseptic conditions; patient identity verification and traceability of the blood product must be assured at every step
Left: sedimentation and leukocyte labelling steps in a tube; early and late leukocyte images; labelled-leukocyte and sulphur-colloid images of a hip prosthesis. Right: trapping of In-111 oxine or Tc-99m HMPAO inside the cell with labelling efficiency, the L/R ratio over time and count profiles of both agents along the stem.
Continuous stream · no seeking
With labelled leukocytes infection shows uptake that rises on late images, and is told from marrow by discordance with colloid.
Source: labelling steps, efficiencies, EANM positivity criterion and dual isotope from the book (24.2). Images, L/R curves and count profiles are representative.
How to use: a single click on the drawing pauses and resumes; in the first step ↑ ↓ or the buttons below switch the agent (In-111 oxine / Tc-99m HMPAO); ← → change steps.
Did this animation help you understand the topic?
Figure 24.5: Positivity criterion in labelled leucocyte scintigraphy: increase in the intensity/size of uptake and in the L/R ratio between early and delayed images (schematic).
Anti-Granulocyte Monoclonal Antibodies (EANM):
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Tc-99m besilesomab (against NCA-95, whole IgG): because it can induce HAMA it is given only once in a lifetime; 400-800 MBq; imaging at 2-4 and 16-24 hours
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Tc-99m sulesomab (Fab' fragment against NCA-90): does not induce HAMA and can be repeated; 740-1110 MBq; imaging at 1 and 4-6 hours
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No blood handling is required; sensitivity and specificity are 83% and 79% in prosthetic infection and 88% and 71% in osteomyelitis
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Positivity: increase of uptake over time or a rise in the T/B ratio of at least 10%; effective dose ~6-6.9 mSv
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Antibody fragment (Fab/Fab') vs whole IgG: fragments clear rapidly from blood, are excreted renally and have low immunogenicity. Whole IgG clears slowly, is excreted hepatically, imaging is done days later and carries a HAMA risk (HAMA may falsely raise CEA and CA-125 immunoassays)
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Attempts at bacteria-specific agents (Tc-99m ciprofloxacin = Infecton, Tc-99m UBI 29-41) have not entered routine use; Infecton is not reliable for distinguishing infection from inflammation because it can also be taken up in sterile inflammation
Indications for Labelled Leucocyte Scintigraphy
Main Indications:
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Acute osteomyelitis (peripheral skeleton)
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Prosthetic infection
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Vascular graft infection
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Abdominal/pelvic infection (abscess)
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Infective endocarditis (together with FDG PET/CT)
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Assessment of inflammatory bowel disease (IBD) activity
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Diabetic foot infection
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Investigation of fever of unknown origin (FUO)
Limitations and False Results:
False Positives:
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Surgical wound (normal postoperative healing)
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GI bleeding (swallowed leucocytes)
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Vascular graft (early postoperative period)
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Accessory spleen
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Tumour (rare)
False Negatives:
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Chronic infection (low leucocyte infiltration)
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Spinal osteomyelitis / discitis → MOST IMPORTANT
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Under antibiotic treatment
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Encapsulated abscess (low leucocyte penetration)
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Leucopenic patient
BOARD TIP
▸
"Is labelled leucocyte scintigraphy reliable in spinal osteomyelitis?"
→ NO! In spinal osteomyelitis/discitis labelled leucocyte scintigraphy may give a false-negative result → normal marrow uptake cannot be distinguished from infection uptake + leucocyte infiltration is low in chronic infection. In spinal infection Ga-67 or FDG PET/CT is preferred.
Dual-Isotope Technique (In-111 Leucocytes + Tc-99m Sulphur Colloid)
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Purpose: to distinguish bone marrow activity from infection uptake
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Principle:
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In-111 labelled leucocytes → taken up both in normal bone marrow and at the site of infection
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Tc-99m sulphur colloid → taken up only in normal bone marrow (not at the site of infection)
•
The two images are compared:
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Concordant: uptake on both studies → normal bone marrow (no infection)
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Discordant: uptake PRESENT on In-111 leucocytes + uptake ABSENT on Tc-99m sulphur colloid → INFECTION
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Use: especially in assessing prosthetic infection and diabetic foot osteomyelitis
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Report content (EANM 2018): in addition to the common items (see 27), antibiotics and drugs that may affect leucocyte migration, labelling and administration method, the standard operating procedure and imaging protocol used (early, delayed and 20-24 hour images, time correction, SPECT/CT). Findings: presence, site, size and intensity of uptake and its change over time (increasing in infection), preferably with semi-quantitative values; factors limiting sensitivity or specificity (motion, metal). The conclusion gives a clear answer to the clinical question, stating the anatomical structures involved and the presence, extent and intensity of infection, and suggests a confirmatory study (e.g. marrow scintigraphy) if needed
BOARD TIP
▸
"How is infection recognised with the dual-isotope technique?"
→ Discordant pattern → uptake PRESENT on In-111 leucocytes + uptake ABSENT on Tc-99m sulphur colloid = infection.
▸
"Concordant pattern?"
→ Uptake on both = normal bone marrow activity (not infection).
Left: sedimentation and leukocyte labelling steps in a tube; early and late leukocyte images; labelled-leukocyte and sulphur-colloid images of a hip prosthesis. Right: trapping of In-111 oxine or Tc-99m HMPAO inside the cell with labelling efficiency, the L/R ratio over time and count profiles of both agents along the stem.
Continuous stream · no seeking
With labelled leukocytes infection shows uptake that rises on late images, and is told from marrow by discordance with colloid.
Source: labelling steps, efficiencies, EANM positivity criterion and dual isotope from the book (24.2). Images, L/R curves and count profiles are representative.
How to use: a single click on the drawing pauses and resumes; in the first step ↑ ↓ or the buttons below switch the agent (In-111 oxine / Tc-99m HMPAO); ← → change steps.
Did this animation help you understand the topic?
Figure 24.6: Dual-isotope technique (In-111 leucocytes + Tc-99m sulphur colloid): concordant pattern = bone marrow, discordant pattern = infection (schematic).
24.3 Infection/Inflammation Imaging with FDG PET/CT8 questions
Basic Principles
FDG Uptake Mechanism (Infection/Inflammation):
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Activated leucocytes (neutrophils, macrophages, lymphocytes) → high glucose metabolism
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Increased GLUT-1 and GLUT-3 transporter expression
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Increased hexokinase activity
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FDG is taken up intensely by activated leucocytes
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Granulation tissue and fibroblasts also take up FDG
Advantages (compared with conventional methods):
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High spatial resolution (4-5 mm)
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Early result (60-90 minutes after injection)
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Whole-body scan in a single session
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Assesses infection, inflammation and malignancy
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Anatomical correlation with the CT component
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Quantitative assessment (SUV)
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No in vitro cell labelling needed
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EANM: in adults 2.5-5.0 MBq/kg (175-350 MBq); in children at least 26 MBq; 19 µSv/MBq, i.e. 3.3-6.7 mSv
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SUV has not been validated in inflammation and infection; in the presence of metal, attenuation-corrected and non-corrected images are assessed together
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Preparation: steroid therapy should be deferred if possible; there is no general recommendation on stopping antibiotics. To suppress myocardial uptake a 48-hour low-carbohydrate diet and ~12 hours of fasting are used
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Indications cited by EANM: sarcoidosis, peripheral osteomyelitis, spinal infection, fever of unknown origin, bacteraemia, endocarditis, vasculitis, malignant external otitis; added value is uncertain in diabetic foot, joint prostheses and IBD
Disadvantages:
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Cannot distinguish infection from malignancy (both take up FDG)
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Postoperative changes → false positive
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High cost
•
Blood glucose control needed in diabetic patients
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Physiological uptake (brain, myocardium, urinary tract, bowel) → may hamper assessment
•
Report content (EANM/SNMMI v2.0): in addition to the common items (see 27), preparation (fasting; myocardial suppression diet for endocarditis or cardiac assessment), blood glucose, antibiotic and corticosteroid use, metallic implants. Findings: intensity and pattern of abnormal uptake (focal, linear, diffuse, heterogeneous), an indication-specific grade where available (e.g. visual grade of vascular uptake relative to liver), the CT correlate; a low-quality study, PET-CT misregistration and metal artefact are stated explicitly (with metal, non-attenuation-corrected images are also reviewed); uptake in regional lymph nodes is not on its own a criterion of infection
Clinical Indications:
The main uses of FDG PET/CT in infection/inflammation:
1. Investigation of fever of unknown origin (FUO) → strongest indication 2. Vascular graft infection 3. Infective endocarditis (especially prosthetic valve) 4. Sarcoidosis (activity assessment, treatment response) 5. Large-vessel vasculitis (Takayasu, giant cell arteritis) 6. Spinal infection (osteomyelitis, discitis, epidural abscess) 7. Detection of metastatic foci of infection (bacteraemia) 8. IgG4-related disease 9. Prosthetic infection (increasing use) 10. Chronic osteomyelitis
BOARD TIP
▸
"Strongest indication of FDG PET/CT in infection imaging?"
→ FUO (fever of unknown origin).
▸
"Best method in spinal osteomyelitis?"
→ FDG PET/CT (labelled leucocytes may be false negative).
▸
"Greatest limitation of FDG PET/CT?"
→ It cannot distinguish infection/inflammation from malignancy.
24.4 Investigation of Fever of Unknown Origin (FUO)2 questions
Definition of FUO
Classic FUO (Petersdorf-Beeson Criteria, modified):
•
Fever >38.3°C
•
Duration >3 weeks
•
No diagnosis after at least 3 days of inpatient or ≥3 outpatient evaluations
Aetiology of FUO (General Distribution):
•
Infection: 20-30% (tuberculosis, abscess, endocarditis, osteomyelitis)
•
Malignancy: 15-25% (lymphoma, leukaemia, solid tumours)
•
Autoimmune/inflammatory: 15-25% (Still disease, SLE, vasculitis)
•
Other/undiagnosed: 20-30%
Nuclear Medicine Methods in FUO
FDG PET/CT → Currently Preferred Method:
•
Highest diagnostic yield in assessing FUO (contributes to diagnosis in 50-70% of cases)
•
Whole-body scan → can detect unexpected foci
•
Assesses infection, malignancy and inflammatory diseases in a single session
•
Negative FDG PET/CT → high negative predictive value → low probability of serious infection/malignancy
•
Recommended early (before a long diagnostic work-up)
Ga-67 Scintigraphy:
•
Historically used in FUO
•
Today largely replaced by FDG PET/CT
•
Disadvantages: long waiting time (48-72 hours), low resolution, high dose
Labelled Leucocyte Scintigraphy:
•
Effective in acute bacterial infections
•
Diagnostic yield in FUO is lower than FDG PET/CT
•
Inadequate in chronic infection and granulomatous diseases
•
In neutropenic patients leucocyte labelling is not suitable, so Ga-67 or FDG is used; persistent uptake in the right lower quadrant (caecum) in neutropenic fever after chemotherapy suggests typhlitis (neutropenic enterocolitis)
BOARD TIP
▸
"Most effective nuclear medicine method in FUO?"
→ FDG PET/CT (50-70% diagnostic contribution).
▸
"If FDG PET/CT is negative?"
→ High negative predictive value → low probability of serious pathology.
▸
"Is Ga-67 still used?"
→ In FUO it has largely been replaced by FDG PET/CT.
24.5 Assessment of Osteomyelitis10 questions
Classification of Osteomyelitis
Acute Osteomyelitis:
•
Duration: <2 weeks
•
Pathogenesis: haematogenous spread (common in children) or direct inoculation (trauma, surgery)
•
Pathology: neutrophilic infiltration, oedema, vascular congestion
•
Timing: bone scintigraphy becomes positive within 24-72 hours of symptoms; because radiographic change requires 30-50% mineral loss, findings appear only at ~10-14 days
•
Most common organism: Staphylococcus aureus
•
In adults haematogenous osteomyelitis is most common in the vertebrae (mostly S. aureus); diabetic foot and pressure ulcer osteomyelitis develops by spread from adjacent soft tissue infection (contiguous route)
Chronic Osteomyelitis:
•
Duration: >6 weeks or recurrent
•
Ga-67 and bone scintigraphy: if Ga-67 uptake is more intense or its distribution is discordant, osteomyelitis is considered. Because bone scintigraphy may remain positive for 1-2 years after healing, treatment response is monitored with Ga-67, leucocytes or FDG
•
Chronic recurrent multifocal osteomyelitis (CRMO): seen in children and adolescents, ~2 times more often in girls; it is a sterile autoinflammatory disease (culture negative, unresponsive to antibiotics). It involves long-bone metaphyses, clavicle, pelvis and vertebrae; whole-body scintigraphy or MRI shows asymptomatic foci; it overlaps with SAPHO
•
In malignant external otitis bone scintigraphy is sensitive for diagnosis but remains positive long after healing; treatment response and when to stop treatment are monitored with Ga-67 (or FDG)
•
Pathology: granulation tissue, fibrosis, sequestrum (necrotic bone), involucrum (new bone formation)
•
Little neutrophil infiltration → labelled leucocyte scintigraphy less sensitive
By Location:
•
Peripheral skeleton (long bones, foot): labelled leucocyte scintigraphy effective
•
Axial skeleton (vertebrae, pelvis): labelled leucocyte scintigraphy unreliable → FDG PET/CT or Ga-67
Imaging Algorithm Uncomplicated Osteomyelitis (Virgin Bone – No Prior Surgery/Trauma):
1. Three-phase bone scintigraphy (Tc-99m MDP) → first step
–
Positive in all three phases → consistent with osteomyelitis
•
Sensitivity: 84-100%, specificity: 70-96%
–
Negative three-phase bone scintigraphy → largely excludes osteomyelitis
2. If three-phase bone scintigraphy is positive but non-specific → labelled leucocyte scintigraphy is added
Complicated Osteomyelitis (Prior Surgery, Fracture, Prosthesis, Neuropathic Joint):
•
Three-phase bone scintigraphy → specificity falls (mechanical changes, postoperative remodelling → false positives)
•
Labelled leucocyte scintigraphy ± bone marrow scintigraphy → preferred
•
Dual-isotope technique (In-111 leucocytes + Tc-99m sulphur colloid) → highest accuracy
Spinal Osteomyelitis / Discitis:
•
Labelled leucocyte scintigraphy → unreliable (false negative, photopenic area)
•
FDG PET/CT → preferred method (sensitivity 96%, specificity 91%)
•
Ga-67 → alternative (if FDG PET/CT is unavailable)
•
MRI → gold standard for anatomical assessment (epidural abscess, soft tissue involvement)
•
Discitis in children: because the disc is vascular in children, infection starts in the disc space; the child presents with limping or refusal to walk, hip, gluteal or back pain and mild fever. Bone scintigraphy shows linear uptake along the end plates of the two adjacent vertebrae
•
Granulomatous spondylitis: the most common cause is tuberculosis (Pott disease; most often lower thoracic, anterior vertebral body involvement, subligamentous spread, relative disc preservation, paravertebral abscess). In brucellosis sacroiliitis and lower lumbar spondylitis are typical. Ga-67 and FDG are positive; labelled leucocytes are unreliable
BOARD TIP
▸
"First step in virgin bone osteomyelitis?"
→ Three-phase bone scintigraphy.
▸
"In complicated osteomyelitis (prosthesis, fracture)?"
→ Labelled leucocytes + bone marrow scintigraphy (dual isotope).
▸
"In spinal osteomyelitis?"
→ FDG PET/CT is preferred → labelled leucocytes are unreliable (false negative).
▸
"Why do labelled leucocytes fail in spinal osteomyelitis?"
→ Normal leucocyte uptake in vertebral bone marrow masks the infection + leucocyte infiltration is low in chronic infection.
Figure 24.7: Osteomyelitis imaging algorithm by clinical situation: uncomplicated, complicated and spinal osteomyelitis.
Did this figure help you understand the topic?
Diabetic Foot Osteomyelitis
•
The diagnosis of osteomyelitis in the diabetic foot is difficult → soft tissue infection, neuropathic changes, Charcot arthropathy → lower the specificity of bone scintigraphy
•
Diabetic foot osteomyelitis mostly occurs in the forefoot adjacent to an ulcer, whereas Charcot neuroarthropathy is most common in the midfoot (tarsometatarsal-Lisfranc); the accuracy of scintigraphy is therefore highest in the forefoot. Visible bone in the ulcer base or a positive probe-to-bone test very probably confirms osteomyelitis
Imaging Approach:
1. Three-phase bone scintigraphy: high sensitivity but low specificity (Charcot, fracture → false positive)
2. Labelled leucocytes + bone marrow scintigraphy (dual isotope): highest accuracy (over 90%)
•
Discordant pattern (In-111 leucocytes +, Tc-99m sulphur colloid −) → infection
–
Concordant pattern (both +) → normal bone marrow or Charcot
3. FDG PET/CT: increasing use, high sensitivity
–
Limited in distinguishing Charcot arthropathy from osteomyelitis (both take up FDG)
–
However, the uptake pattern and intensity may give clues
4. MRI: superior for assessing soft tissue and bone marrow → anatomical gold standard
Charcot Arthropathy vs Osteomyelitis:
| Feature | Osteomyelitis | Charcot Arthropathy |
|---|---|---|
| Three-phase bone scintigraphy | Positive (3 phases) | Positive (3 phases) → cannot differentiate |
| Labelled leucocytes | Positive (focal) | Usually negative (if no infection) |
| Dual isotope | Discordant | Concordant |
| FDG PET/CT | Intense uptake | Moderate uptake (hard to differentiate) |
| MRI | Bone marrow oedema + soft tissue abscess | Bone marrow oedema + joint destruction |
BOARD TIP
▸
"Best method to distinguish osteomyelitis from Charcot in the diabetic foot?"
→ Labelled leucocytes + bone marrow scintigraphy (dual isotope) → over 90% accuracy.
▸
"Can three-phase bone scintigraphy differentiate?"
→ NO → both are positive in all three phases.
▸
"How does Charcot appear with the dual-isotope technique?"
→ Concordant pattern → uptake on both studies (bone marrow activation).
24.6 Assessment of Prosthesis/Graft Infection3 questions
Prosthetic Infection
General Information:
•
Incidence of joint prosthesis infection: 1-2% after primary arthroplasty
•
After revision surgery: 3-5%
•
Most common organisms: Staphylococcus aureus, coagulase-negative staphylococci
•
Clinical classification:
•
Early infection (<3 months): acute, virulent organisms
•
Delayed infection (3-24 months): low-virulence organisms
•
Late infection (>24 months): haematogenous spread
Diagnostic Difficulty:
•
Normal postoperative changes around the prosthesis (bone remodelling, periprosthetic reactive changes) → false positives on bone scintigraphy
•
Distinguishing aseptic from septic loosening is critical → treatment approaches differ
Imaging Methods
Three-Phase Bone Scintigraphy:
•
High sensitivity (90-100%) → if negative, largely excludes infection
•
Low specificity (30-40%) → aseptic loosening, heterotopic ossification, stress fracture → false positives
•
Increased uptake around the prosthesis may be normal for up to 2 years (especially with uncemented prostheses)
•
Used as a screening test → if negative, no further study is needed
Labelled Leucocyte Scintigraphy:
•
More specific than bone scintigraphy
•
But insufficient alone → bone marrow distribution around the prosthesis may be altered → false positives
•
Should be used together with bone marrow scintigraphy (dual isotope)
Dual-Isotope Technique (Labelled Leucocytes + Bone Marrow Scintigraphy):
•
Gold-standard nuclear medicine method → for diagnosing prosthetic infection
•
Accuracy: 88-98%
•
Principle:
–
Bone marrow distribution changes around the prosthesis (after surgery)
–
Labelled leucocytes are also taken up in altered bone marrow → false positives
–
Comparison with bone marrow scintigraphy (Tc-99m sulphur colloid) → distinguishes true infection
–
Discordant pattern → infection
–
Concordant pattern → bone marrow activation (not infection)
FDG PET/CT:
•
Increasing use in prosthetic infection
•
High sensitivity (85-95%)
•
Variable specificity (70-90%) → metal artefact, aseptic inflammation → false positives
•
The periprosthetic FDG uptake pattern is important:
–
Focal intense uptake at the bone-prosthesis interface → suggests infection
–
Diffuse mild uptake along the prosthesis → aseptic loosening or normal postoperative change
•
Metal artefact → CT attenuation correction error → SUV values may be unreliable
BOARD TIP
▸
"Gold-standard nuclear medicine method in prosthetic infection?"
→ Labelled leucocytes + bone marrow scintigraphy (dual isotope) → accuracy 88-98%.
▸
"If three-phase bone scintigraphy is negative?"
→ Largely excludes infection (high sensitivity, low specificity → screening test).
▸
"Infection pattern on FDG PET/CT?"
→ Focal intense uptake at the bone-prosthesis interface.
Figure 24.8: FDG uptake patterns around a hip prosthesis: diffuse mild in aseptic loosening, focal intense at the interface in infection (schematic).
Did this figure help you understand the topic?
Aseptic vs Septic Loosening
| Feature | Aseptic Loosening | Septic Loosening (Infection) |
|---|---|---|
| Three-phase bone scintigraphy | Positive (periprosthetic uptake in the delayed phase) | Positive (in 3 phases) → cannot differentiate |
| Labelled leucocytes | Usually negative or mild | Positive (focal intense) |
| Dual isotope | Concordant | Discordant |
| FDG PET/CT | Diffuse mild uptake | Focal intense uptake |
| CRP/ESR | Normal or mildly raised | Markedly raised |
24.7 Infective Endocarditis and Vascular Graft Infection5 questions
Infective Endocarditis
General Information:
•
Infection of the heart valve endothelium → vegetation formation
•
Most common organisms: Streptococcus viridans (native valve), Staphylococcus aureus (prosthetic valve, IV drug users)
•
Diagnosis: modified Duke criteria (major and minor criteria)
Role of Nuclear Medicine Methods:
•
The 2015 ESC guideline added multimodality imaging to the diagnostic criteria. ESC 2023: FDG PET/CT(A) and labelled leucocyte SPECT/CT are a major diagnostic criterion when they show lesions characteristic of IE on native or prosthetic valves or intracardiac foreign material; asymptomatic emboli detected by imaging count as a minor criterion. Intense focal or heterogeneous uptake around a prosthetic valve is a major criterion irrespective of the time since surgery (the former 3-month condition was dropped; proper interpretation criteria are essential)
FDG PET/CT – Prosthetic Valve Endocarditis:
•
Most valuable in prosthetic valve endocarditis
•
Limited role in native valve endocarditis (physiological myocardial FDG uptake → hampers assessment); according to ESC 2023 sensitivity is ~31% and specificity ~98%, and absent uptake does not exclude the diagnosis. Focal uptake in the valve plane, regardless of intensity, favours native valve IE; it is valuable for showing septic emboli and the source of bacteraemia (EANM/SNMMI 2024)
•
Patient preparation is critical: to suppress myocardial FDG uptake:
–
Prolonged fasting (≥12-18 hours) → shift to free fatty acid metabolism
–
Low/no-carbohydrate, high-fat diet for 24-48 hours, followed by at least 12 hours of fasting (EANM/SNMMI 2024); despite adequate preparation the myocardium is not suppressed in 5-20% of patients
–
IV unfractionated heparin (in some protocols; 50 IU/kg, 15 min before FDG) → raises free fatty acid levels
•
Focal/heterogeneous intense FDG uptake around a prosthetic valve → suggests infection
•
Homogeneous diffuse uptake → sterile postoperative inflammation; it can persist indefinitely (EANM/SNMMI 2024). Surgical adhesives can cause focal uptake; in equivocal cases a positive leucocyte SPECT/CT confirms the diagnosis, whereas a negative one does not exclude it
•
Sensitivity: 73-97% (prosthetic valve), specificity: 71-100%; in the most recent meta-analysis sensitivity 86% and specificity 84% (ESC 2023). Adding CT angiography (PET/CTA) reduces equivocal cases
•
Added value: detection of septic emboli (brain, spleen, kidney, vertebra, peripheral) → advantage of whole-body scanning
Labelled Leucocyte SPECT/CT:
•
Alternative method in prosthetic valve endocarditis
•
More specific than FDG PET/CT (no physiological myocardial uptake)
•
But lower sensitivity and spatial resolution
•
Limited in detecting small vegetations
BOARD TIP
▸
"When is FDG PET/CT used in endocarditis?"
→ In prosthetic valve endocarditis → a major diagnostic criterion (added by ESC 2015; in ESC 2023 it also covers native valves and devices and, for prosthetic valves, applies irrespective of the time since surgery).
▸
"In native valves?"
→ Limited role (myocardial FDG uptake).
▸
"To suppress myocardial uptake?"
→ ≥12-18 hours of fasting + low-carbohydrate/high-fat diet.
▸
"Additional advantage of FDG PET/CT?"
→ Detection of septic emboli by whole-body scanning.
Vascular Graft Infection
General Information:
•
Incidence of vascular graft infection: 1-6%
•
High mortality (25-75%)
•
Most common: aortic grafts (abdominal > thoracic)
•
Most common organisms: S. aureus, S. epidermidis, gram-negative bacilli
FDG PET/CT:
•
Most valuable imaging method in vascular graft infection
•
Sensitivity: 93-100%, specificity: 70-91%
•
Focal/heterogeneous intense FDG uptake → infection
•
Diffuse homogeneous mild uptake → sterile inflammation or foreign-body reaction; depending on the material it can persist indefinitely. In the first 4 months after surgery false positives can occur because sterile inflammation is hard to separate from infection or thrombosis (EANM/SNMMI 2024)
•
Gas bubbles around the graft (on CT) + FDG uptake → highly specific for infection
•
Low-grade infection → FDG uptake may be low → risk of false negative
•
Visual scales (none universally accepted): scores 3-5 on the 5-point scale and 4-6 on the 6-point scale favour vascular graft infection (EANM/SNMMI 2024)
Uptake Patterns:
| Pattern | Interpretation |
|---|---|
| Focal intense uptake | Suggests infection |
| Diffuse mild uptake | Sterile inflammation/foreign-body reaction (may persist indefinitely; false positives in the first 4 months) or low-grade infection |
| No uptake | Low probability of infection |
| Focal uptake + perigraft fluid/gas (CT) | Highly specific for infection |
Labelled Leucocyte Scintigraphy:
•
Alternative method in vascular graft infection
•
More specific than FDG PET/CT but less sensitive
•
Risk of false positives in the early postoperative period (normal healing)
CT Angiography:
•
Anatomical assessment → perigraft fluid, gas, pseudoaneurysm
•
Gives no functional information → combined assessment with FDG PET/CT is optimal
BOARD TIP
▸
"Most valuable imaging in vascular graft infection?"
→ FDG PET/CT (sensitivity 93-100%).
▸
"Gas around the graft + FDG uptake?"
→ Highly specific for infection.
▸
"For how long postoperatively may FDG uptake be normal?"
→ Diffuse homogeneous uptake may persist indefinitely; false positives can occur in the first 4 months (EANM/SNMMI 2024).
24.8 Sarcoidosis and Granulomatous Diseases8 questions
Sarcoidosis
General Information:
•
Non-caseating granulomatous disease
•
Aetiology unknown
•
Most commonly involved organs: lung (90%), lymph nodes, skin, eye, liver, spleen, heart, nervous system
•
Bone involvement is rare (1-13%) and most common in the phalanges of the hands and feet (lace-like lytic lesions); bone scintigraphy shows focal increased uptake, and FDG PET/CT can also show lesions in the axial skeleton
•
Diagnosis: clinical + radiological findings + non-caseating granuloma (biopsy) + exclusion of other causes
Nuclear Medicine Methods:
Ga-67 Scintigraphy (Historical)
•
Classic patterns in sarcoidosis:
–
"Panda" sign: bilateral parotid + lacrimal gland uptake
–
"Lambda" (λ) sign: bilateral hilar + right paratracheal lymph node uptake
–
Panda + Lambda → highly specific for sarcoidosis (99%)
•
Today largely replaced by FDG PET/CT
•
Situations where Ga-67 may still be used: centres where FDG PET/CT is not available
FDG PET/CT – Sarcoidosis
Indications:
1. Assessment of disease activity → active granulomatous inflammation takes up FDG 2. Monitoring of treatment response → FDG uptake falls with treatment 3. Detection of occult disease foci → unexpected organ involvement 4. Choice of biopsy site → the most active lesion is targeted 5. Assessment of cardiac sarcoidosis 6. Assessment of neurosarcoidosis
FDG PET/CT Findings:
•
Intense FDG uptake in bilateral hilar and mediastinal lymph nodes
•
Nodular or diffuse uptake in the lung parenchyma
•
Extrathoracic involvement: liver, spleen, bone, bone marrow, skin, eye, salivary glands
•
FDG uptake falls with treatment → valuable for monitoring treatment response
Sarcoidosis vs Lymphoma:
•
Both show bilateral hilar/mediastinal lymphadenopathy + FDG uptake
•
Differentiation may be difficult → biopsy needed
•
In sarcoidosis: symmetric uptake, "Lambda" pattern, extrathoracic uptake pattern
•
In lymphoma: asymmetric uptake, conglomerate mass, more marked splenic involvement
Cardiac Sarcoidosis
Importance:
•
Cardiac involvement in 5-25% of sarcoidosis patients
•
May be clinically silent → risk of sudden cardiac death
•
Conduction disturbances, ventricular arrhythmias, heart failure
FDG PET/CT – Cardiac Sarcoidosis Protocol:
•
Patient preparation is critical → physiological myocardial FDG uptake must be suppressed
–
≥12-18 hours of fasting (preferably ≥18 hours)
–
Focal-on-diffuse FDG uptake → may be active sarcoidosis, but may be confused with inadequate myocardial suppression → patient preparation is critical
•
In some protocols: IV heparin (50 IU/kg, 15 min before imaging)
•
Purpose: to shift the myocardial energy source from glucose to free fatty acids → physiological FDG uptake is suppressed
•
Perfusion PET (Rb-82 or N-13 ammonia) + FDG PET are performed together
•
EANM/SNMMI 2024: with poor suppression, diffuse, isolated homogeneous basal lateral wall, papillary muscle or basal 'ring' uptake is usually physiological; sarcoidosis gives focal or focal-on-diffuse uptake. In patients not on anti-inflammatory therapy the sensitivity of FDG is similar to that of MRI
Cardiac Sarcoidosis – Uptake Patterns:
| Pattern | Perfusion | FDG | Interpretation |
|---|---|---|---|
| Normal | Normal | No uptake | No active cardiac sarcoidosis |
| Early inflammation | Normal | Focal/focal-on-diffuse uptake | Active inflammation (no scar yet) |
| Advanced disease | Defect | Focal uptake (in the defect region) | Active inflammation + scar |
| Burned-out (end stage) | Defect | No uptake | Scar (no active inflammation) |
•
Perfusion defect + FDG uptake (mismatch) → the most specific pattern for active cardiac sarcoidosis
•
Low-carbohydrate (<5 g), high-fat diet (dinner the evening before and breakfast)
BOARD TIP
▸
"Most specific FDG PET/CT finding in cardiac sarcoidosis?"
→ Perfusion defect + focal FDG uptake (mismatch).
▸
"To suppress myocardial FDG uptake?"
→ ≥18 hours of fasting + low-carbohydrate/high-fat diet + IV heparin.
▸
"Burned-out cardiac sarcoidosis?"
→ Perfusion defect PRESENT + FDG uptake ABSENT → scar, no active inflammation.
▸
"Focal-on-diffuse uptake?"
→ May be active sarcoidosis BUT may be confused with inadequate myocardial suppression → question the patient preparation.
Figure 24.9: Combined interpretation of perfusion and FDG PET findings in cardiac sarcoidosis (schematic).
Did this figure help you understand the topic?
Large-Vessel Vasculitis
Takayasu Arteritis:
•
Granulomatous vasculitis of the aorta and its main branches
•
Common in young women (<40 years)
•
FDG PET/CT → can detect vascular inflammation early (prestenotic phase)
•
Diffuse linear FDG uptake in the aortic wall → active vasculitis
•
Valuable for monitoring treatment response
Giant Cell (Temporal) Arteritis:
•
>50 years, temporal headache, jaw claudication, risk of visual loss
•
FDG PET/CT → can show large-vessel involvement (aorta, subclavian, carotid)
•
Temporal artery involvement → resolution was limited on older scanners; with digital PET the cranial arteries (temporal, occipital, facial) can be assessed reliably: 0 no uptake, 1 just above surrounding tissue, 2 clearly above; grade ≥1 is positive (EANM/SNMMI 2026)
•
Frequently associated with polymyalgia rheumatica → FDG uptake around the shoulders and hips
FDG PET/CT – Assessment of Vasculitis:
•
Vascular FDG uptake is compared with liver uptake:
•
Grade 0: no vascular uptake
•
Grade 1: vascular uptake < liver
•
Grade 2: vascular uptake ≈ liver → possibly vasculitis; on newer digital PET it is seen in many patients without vasculitis, so it is interpreted with caution (EANM/SNMMI 2026)
•
Grade 3: vascular uptake > liver → active vasculitis
•
EANM/SNMMI 2026 (vasculitis and PMR): grade 3 in at least one segment of the aorta or a major branch is positive on all systems; grades 0-1 are negative. In suspected large-vessel GCA, Takayasu arteritis and PMR, glucocorticoids are started after PET when feasible; in cranial GCA treatment is not delayed because of the risk of ischaemia. If glucocorticoids cannot be withheld, PET is performed within the first 3 days; in suspected PMR they may be paused for 1 week if appropriate. Fasting 4 (ideally 6) hours, blood glucose <7 mmol/L (126 mg/dL), otherwise <11 mmol/L; 2-3 MBq/kg; standard uptake 60 min (delayed 90-180 min images improve contrast); vertex to knees, arms by the sides. PMR: shoulder and pelvic girdles and cervical and lumbar interspinous regions are graded 0-2; a Leuven score ≥16 or a Leuven/Groningen score ≥8 is positive
•
Atherosclerosis → focal/segmental vascular FDG uptake → may be confused with vasculitis
–
In atherosclerotic plaque FDG accumulates mainly in inflammatory macrophages (plaque inflammation and vulnerability); active microcalcification is shown with F-18 NaF
•
Vasculitis → diffuse, smooth, linear uptake; atherosclerosis → focal, irregular uptake
BOARD TIP
▸
"Role of FDG PET/CT in large-vessel vasculitis?"
→ Detects vascular inflammation early (prestenotic phase) → CT/MR angiography may still be normal.
▸
"Vasculitis vs atherosclerosis?"
→ Vasculitis: diffuse smooth linear uptake; atherosclerosis: focal irregular uptake.
▸
"How is vascular uptake graded?"
→ Comparison with the liver → Grade 3 (vascular > liver) = active vasculitis.
Figure 24.10: Grading of vascular FDG uptake relative to the liver in large-vessel vasculitis and the difference between vasculitis and atherosclerosis patterns (schematic).
Did this figure help you understand the topic?
Other Granulomatous Diseases
•
Tuberculosis: FDG PET/CT → intense FDG uptake in active TB, monitoring of treatment response, detection of extrapulmonary TB foci
•
Fungal infections: histoplasmosis, coccidioidomycosis → granulomatous response → FDG uptake
•
Wegener granulomatosis (GPA): upper and lower respiratory tract + renal involvement → activity assessment with FDG PET/CT
•
Crohn disease: transmural granulomatous inflammation → assessment of activity and extent with FDG PET/CT
Key Points for the Board
Ga-67 Scintigraphy:
•
Uptake mechanism: multiple → transferrin, lactoferrin, siderophores (bacteria-specific), leucocyte uptake
•
Half-life: 78.3 hours, gamma energies: 93, 185, 300, 394 keV
•
Imaging: 48-72 hours after injection, medium-energy collimator
•
Normal biodistribution: liver > spleen > bone marrow + kidney (early) + bowel (late)
•
Sarcoidosis patterns: Panda (parotid + lacrimal) + Lambda (bilateral hilar + right paratracheal) → together highly specific
•
Today replaced by FDG PET/CT for many indications
Labelled Leucocyte Scintigraphy:
•
In-111 oxine: NO kidney/bladder uptake, NO bowel uptake (up to 24 hours) → preferred for abdominal infection
•
Tc-99m HMPAO: kidney/bladder uptake PRESENT, bowel uptake PRESENT → better image quality, same-day result
•
Dual isotope (In-111 leucocytes + Tc-99m sulphur colloid): discordant = infection, concordant = bone marrow
•
Unreliable in spinal osteomyelitis → false negative → FDG PET/CT is preferred
Osteomyelitis Algorithm:
•
Virgin bone: three-phase bone scintigraphy (first step) → if positive, labelled leucocytes
•
Complicated (prosthesis, fracture, Charcot): labelled leucocytes + bone marrow (dual isotope) → gold standard
•
Spinal: FDG PET/CT is preferred (labelled leucocytes unreliable)
•
Diabetic foot: dual isotope → over 90% accuracy → best for Charcot vs osteomyelitis
FDG PET/CT – Infection/Inflammation:
•
Strongest indication: FUO (50-70% diagnostic contribution)
•
Negative FDG PET/CT → high negative predictive value
•
Most important limitation: cannot distinguish infection from malignancy
•
In spinal osteomyelitis: sensitivity 96%, specificity 91%
Prosthetic Valve Endocarditis:
•
FDG PET/CT → added to the Duke criteria as a major criterion (2015 ESC)
•
Myocardial suppression: ≥12-18 hours fasting + low-carbohydrate/high-fat diet + IV heparin
•
Limited role in native valves (physiological myocardial uptake)
•
Added value: whole-body scanning for septic emboli
Vascular Graft Infection:
•
FDG PET/CT → most valuable method (sensitivity 93-100%)
•
Focal uptake + perigraft gas → highly specific for infection
•
Diffuse mild uptake may be normal in the first 4-8 weeks postoperatively
Cardiac Sarcoidosis:
•
Most specific pattern: perfusion defect + focal FDG uptake (mismatch)
•
Burned-out: perfusion defect + NO FDG uptake → scar
•
Myocardial suppression: same as the endocarditis protocol
•
Focal-on-diffuse uptake → may be active sarcoidosis BUT may be confused with inadequate suppression
Large-Vessel Vasculitis:
•
FDG PET/CT → detects vascular inflammation early (prestenotic phase)
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Grading: comparison with the liver → Grade 3 (vascular > liver) = active vasculitis
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Vasculitis: diffuse smooth linear uptake; atherosclerosis: focal irregular uptake
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Takayasu: young woman <40 years; giant cell arteritis: >50 years, temporal + large vessels
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Ga-67: critical organ colon; marked bilateral renal uptake after 24 hours is pathological → acute interstitial nephritis (not expected in ATN)
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With In-111-WBC the critical organ (highest dose) is the spleen
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Normal chest radiograph + diffuse bilateral lung Ga-67 uptake → PCP; Kaposi sarcoma Ga-67-negative/Tl-201-positive
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In IBD early imaging with Tc-99m HMPAO-WBC (30 min–2-3 hours) is essential → after that physiological bowel activity misleads
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In acute osteomyelitis bone scintigraphy becomes positive at 24-72 hours; radiography at ~10-14 days
Additional Notes from EANM Guidelines:
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WBC: Tc-99m-WBC 185-370 MBq, In-111-WBC 10-18 MBq; positivity = uptake increasing over time; In-111-WBC preferred in the abdomen
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Anti-granulocyte MoAb: besilesomab (NCA-95, HAMA → single administration), sulesomab (NCA-90, Fab', no HAMA)
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Infection FDG: 175-350 MBq; SUV not validated; steroids deferred; no recommendation to stop antibiotics
Current guidelines on this chapter's topics
The latest guidelines and consensus documents on the procedures covered in this chapter (official EANM index and primary sources, November 2026). Comparison of the text with these versions is in progress; consult the guideline itself for details.
- 2026Updated procedural guideline/procedure standard [18F]FDG-PET/CT(A) in large vessel vasculitis and polymyalgia rheumatica of the EANM, SNMMI, ASNC, CANM, ANZSNM and endorsed by the CSNM (opens in a new tab)
- 2024EANM/SNMMI guideline/procedure standard for [18F]FDG hybrid PET use in infection and inflammation in adults v2.0 (opens in a new tab)
- 2024EANM consensus document on the use of [18F]FDG PET/CT in fever and inflammation of unknown origin (opens in a new tab)
- 2024Diagnostic imaging of the diabetic foot: an EANM evidence-based guidance (opens in a new tab)
- 20232023 ESC Guidelines for the management of endocarditis: Developed by the task force on the management of endocarditis of the European Society of Cardiology (ESC) (opens in a new tab)
- 2022Evidence-based guideline of the European Association of Nuclear Medicine (EANM) on imaging infection in vascular grafts (opens in a new tab)
- 2019Joint EANM/ESNR and ESCMID-endorsed document for the diagnosis of spine infection (spondylodiscitis) in adults (opens in a new tab)
- 2019Consensus document for the diagnosis of prosthetic joint infections: a joint paper by the EANM, EBJIS, and ESR (with ESCMID endorsement) (opens in a new tab)
- 2019Consensus document for the diagnosis of peripheral bone infection in adults: a joint paper by the EANM, EBJIS, and ESR (with ESCMID endorsement) (opens in a new tab)
- 2018Clinical indications, image acquisition and data interpretation for white blood cells and anti-granulocyte monoclonal antibody scintigraphy (opens in a new tab)
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