IAEA RTC – Hybrid Imaging: SPECT/CT, PET/CT, and Sentinel

Lymph Node Detection

Hybrid Imaging of Infection

Giuliano Mariani

Regional Center of Nuclear Medicine

University of Pisa, Pisa, Italy

Parnu (Estonia), October 6 – 10, 2014

Inflammation ….. a long story

sh me me t

Shememet = inflammation

Smith Papyrus, circa 1650 B.C.

Time after single injury, days

Re

lati

ve

am

ou

nt Edema

Neutrophils

Monocytes/Macrophages

Acute Infection/Inflammation

granulocytes IgM macrophagescitokines

1 2 32

Nuclear Medicine Imaging of Acute

Infection/Inflammation

99mTc-HMPAO-WBC111In-oxine-WBC[18F]FDGAnti-granulocyte MoAb

67Ga-citrate68Ga-citrate

IL-8

18F-FDG

99mTc-Antibiotics111In-VitaminsAntimicrobial peptides

Chronic Infection/Inflammation

67Ga-citrate68Ga-citrate

Nuclear Medicine Imaging of Chronic

Infection/inflammation

[18F]FDG

Moab anti-TNF,IL-2

IL-8 (acute)

IL-1 (chronic)

IL-2 (chronic)

Moab anti-

TNF

Nuclear Medicine Imaging of Infection

INDIRECT: by targeting the host immune system, proteins, cytokines and hypermetabolic activity

DIRECT: by targeting the bacteria

67Ga-citrate68Ga-citrate

Labelled

leukocytes

MoAb anti-

granulocytes

Labelled

antibioticsLabelled

antimicrobial

peptides

Labelled

vitamins

[18F]FDG

HIG

99mTc-HMPAO-leukocytes

Nuclear Medicine for Indirect Imaging of Infection

Standard Protocol of 99mTc-HMPAO-Leukocyte scintigraphy:

Labelling of leukocytes with 99mTc-HMPAO according to EANM guidelines

(www.eanm.org)

I.v. injection of 99mTc-HMPAO-Leukocytes (370-740 MBq).

Total-body and planar images at 30 min, planar and/or SPECT/CT at 4 hr

and 24 hr.

Advantages: high sensitivity and specificity (except for spine infection).

Limitations: time-consuming, need for specialized staff.

Active chemotaxis in infectious foci

Planar images (anterior and lateral) of 99mTc-

HMPAO-Leukocyte scintigraphy in patient with

vascular (aorto-bifemoral) prosthesis 30 min (left)

and 4 hr (right) p.i.

[18F]FDG Overexpression of Glut-I and Glut-III on the surface of the

inflammatory cells and activated leukocytes

K1

K2

Standard Protocol of [18F]FDG PET/CT:

I.v. injection of 3.5 MBq/kg [18F]FDG

Total-body PET/CT acquisition at 1 hr p.i.

Advantages: high sensitivity

Limitations: low specificity

Follow-up with [18F]FDG PET/CT

in patient with right hip prosthesis

implanted after surgical removal of

femoral head, site of metastasis

from breast cancer.

Nuclear Medicine for Indirect Imaging of Infection

67Ga-citrate68Ga-citrate

Standard Protocol of 68Ga-citrate PET/CT

I.v. injection of 68Ga-citrate (2-3 MBq/kg)

PET/CT acquisition at 1 hr

Advantages: total-body evaluation, short interval before acquisition

Limitations: low specificity

Presence of lactoferrin, transferrin, albumin and cells in

inflammatory tissues; presence of bacterial siderophores

Nanni et al, J Nucl Med. 2010;51:1932-6.

MRI and 68Ga-citrate PET/CT in patient

with diskitis. MRI shows abnormal signal

in L5-S1, equivocal for infective diskitis.

68Ga-citrate PET/CT shows focal area of

increased tracer uptake consistent with

inflammation (SUVmax 5.3).

Nuclear Medicine for Indirect Imaging of Infection

Labelled antimicrobial peptides:99mTc-Ubiquicidin 29-41

Radiopharmaceuticals for Direct Imaging of Infection

Criteria for interpretation: images acquired at 30, 60 (and 120) min

are considered for interpretation, since at 240 min tracer uptake is

markedly reduced.

The target is represented by bacteria

Labelled vit. H (Biotin)Locally increased capillary permeability

(edema), but also growth factor for bacteria

Soft tissue infection by Propionibacterium with minimal bone involvement

Nuclear Medicine for Direct/Indirect Imaging of Infection

So … Which Radiopharmaceutical?

[18F]FDG

The right answer depends on:

1) Region of the body to be explored

2) activity of disease (acute, chronic, subacute)

Disease Radiopharmaceutical

Acute infection Labelled leukocytes

[18F]FDG

Chronic infection 67Ga-citrate

[18F]FDG

So … Which Radiopharmaceutical?

Region of interest Agent Acquisition Imaging

Heart Labelled leukocytes (WBC)[18F]FDG

30’, 4 h, 24 h1 h

Total-body (FUO)High probability

Low probability

Labelled leukocytes[18F]FDG

30’, 4 h, 24 h1 h

Large vessel vasculitis [18F]FDG 1 h

CNS Labelled leukocytes 30’, 4 h, 24 h

Bone and Joint :Low probability

High probability Dynamic bone scanLabelled leukocytes 30’, 4 h, 24 h

Spine 67Ga-citrate (+ bone scan)[18F]FDG

6h, 24 h, 48 h1 h

Bowel Labelled leukocytes 30’ and 2 hr

Foot (diabetic foot) Labelled leukocytes 30’, 4 h, 24 h

Vascular prosthesisChest

Abdomen

Labelled leukocytesLabelled leukocytes[18F]FDG

30’, 4 h, 24 h30’, 4 h1 h

SPECT/CT is recommendedPET/CT is recommended

SPECT/CT according to ROI

PET/CT is recommended

PET/CT is recommended

Planar SPECT/CT if necessary

PlanarSPECT/CT if necessary

SPECT/CT is recommendedPET/CT is recommended

PlanarSPECT/CT if necessary

SPECT/CT is recommended

SPECT/CT is recommended

PET/CT is recommended

NM Imaging of Infection/Inflammation

Jutte P, Lazzeri E, Sconfienza LM,

Cassar-Pullicino V, Trampuz A, Petro-

sillo N, Signore A.

Diagnostic flowcharts in osteomyelitis,

spondylodiscitis and prosthetic joint

infection.

Q J Nucl Med Mol Imaging 2014;58:2-19.

Some Practical Considerations

Regarding Hybrid Imaging of Infection

Clinical problems:

1. Is infection present?

1. If YES, is exact anatomic localization

of infection likely to impact on clinical

treatment?

Definite Impact on Treatment (1)

Osteomyelitis:

Is infection limited to bone or does it involve

adjacent soft tissues?

Diabetic foot infection:

Is infection involving soft tissues only or does

it involve bone(s) as well?

Joint prosthesis:

Is infection involving the bone only, bone and

soft tissues, or soft tissues only?

Definite Impact on Treatment (2)

Spine infection (non-operated/post-surgery):

Is infection involving the vertebral body, body

and disc, or involving soft tissues as well?

Is the hardware involved, at different levels?

Cardiovascular infection:

Endocarditis on native valves?

Endocarditis on prosthetic valves

(mechanical/biological)?

Is septic embolism present?

Implanted electrical devices (surgical pocket,

intravascular leads, intracardiac leads).

Prosthetic vascular grafts.

Peripheral bone

Osteomyelits (Bone Infection)

Spine (SD)

Joint prosthesis

Planar SPECT/CT

Calcaneal bone osteomyelitis

High probability of Acute OM:99mTc-HMPAO-WBC

High probability of Acute OM:

Leukoscan®

Soft tissue infection without bone infection

Planar SPECT/CT

Bone and soft tissue infection

High probability of Acute OM:99mTc-HMPAO-WBC

Planar SPECT/CT

SPECT/CT

Hardware infection by St. Epidermidis

High probability of Acute OM:99mTc-HMPAO-WBC

30 min p.i. 4 h p.i. 24 h p.i.

Joint infection by St. Aureus

High probability of Acute Joint Infection:99mTc-HMPAO-WBC

Soft tissue infection

High probability of Acute Prosthetic Joint

Infection: 99mTc-HMPAO-WBC

Planar SPECT/CT

November 2011

July 2012

March 2012

Prosthetic Joint Infection: Evaluation of

Response with 99mTc-HMPAO-WBC

Reinartz classification

Prosthetic Joint Infection: [18F]FDG PET/CT

Pattern 1 Pattern 2 Pattern 3a

Pattern 4a Pattern 4b Pattern 5

No loosening

Loosening

Reinartz P. Q J Nucl Med Mol Imaging 2009;53:41-50

Prosthetic Joint Infection: [18F]FDG PET/CT

Bone and Joint Infection

Meta-analysis of 87 studies (1984-2004): WBC scintigraphy has

excellent diagnostic accuracy (up to 89%) with sensitivities and

specificities ranging from 83% to 89% and 84% to 90%,

respectively.

(Prandini N et al. Nucl Med Commun. 2006;27:633-44)

SPECT/CT can improve imaging with WBC in patients with

suspected osteomyelitis by providing accurate anatomic

localization and precise definition of the extent of infection.

(Filippi L et al. J Nucl Med

2006;47:1908-13)

WBC scintigraphy remains the gold standard technique for

diagnosing neutrophil-mediated processes. WBC/bone marrow

scintigraphy is currently the modality of choice for diagnosing

prosthetic joint infection. PET will receive full acceptance only

when specific [18F]FDG uptake patterns can be validated.(Gemmel F et al.

Eur J Nucl Med Mol Imaging. 2012; 39:892–909)

Onset and diffusion

of hematogenous

spinal infection

Possible onset and

diffusion of post-

surgery/intervention

spinal infection

Vertebral Osteomyelitis (SD)

Low probability of SD

• 99mTc-MDP Bone scan

High probability of SD

• 67Ga+99mTc-MDP

• [18F]FDG PET/CT

High probability of SD

• 67Ga-citrate + 99mTc-MDP

• [18F]FDG PET/CT

Vertebral Osteomyelitis: [18F]FDG-PET/CT

SD at L4 (Propionibacterium) and at C7 (MR St. Aureus)

MRI

Vertebral Osteomyelitis: [18F]FDG-PET/CT

bone biopsy

Bone metastasis from melanoma

111In-DTPA-Biotin[18F]FDG

Infection of the cervical spine

A systematic review of the literature (1984-2004) indicates that

the accuracy of infection tracers used for spondylodiscitis

varies from 62% to 90%.(Prandini N et al. Nucl

Med Commun. 2006;27:633-44)

“FDG-PET is a promising alternative to bone/gallium imaging.

The advantages of the procedure are obvious: the study is

sensitive, it is completed in a single session and image

resolution is superior to that obtained with single-photon-

emitting tracers. As with gallium, however, specificity remains

an issue.

While FDG uptake in uninfected fractures may normalise sooner

than gallium or diphosphonate uptake, differentiating infection

from tumour will be problematic.“(Gemmel F. Eur J Nucl Med Mol

Imaging 2006;33:1226–1237)

Vertebral Osteomyelitis (SD)

Region of interest Radiopharmaceuticals Acquisition Imaging

Peripheral bone infections

Low probability

High probability Dynamic bone scanLabelled leukocytes

3 h30’, 4 h, 24 h

Joint infection and prosthetic joint infection

Low probability

High probability Dynamic bone scanLabelled leukocytes

3 h30’, 4 h, 24 h

Spine infections

Low probability

High probability Bone scan67Ga-citrate (+ bone scan)[18F]FDG PET

3 h6 h, 24 h. 48h1 h

PlanarSPECT/CT if necessary

PlanarSPECT/CT if necessary

SPECT/CT is recommendedPET/CT is recommended

Nuclear Medicine Imaging of

Osteomyelitis

Imaging for Suspected

Postoperative Spondylodiscitis

• Radiography

• Computed Tomography

• Magnetic Resonance Imaging

• Bone scintigraphy

• SPECT, SPECT/CT

• PET, PET/CT

Sumer J et al. SPECT/CT in patients with lower back pain

after lumbar fusion surgery (LFS). Nucl Med Commun 2013

• Retrospective study in 37 patients with lower back pain

after LFS: three-phase bone scan and delayed

SPECT/CT.

• Five diagnostic categories:

1) metal loosening

2) insufficient stabilization of metal implants

3) adjacent instability for degenerative disease

4) indeterminate

5) normal

• Normal scan in 8/37 patients.

• 62 abnormal foci by planar/SPECT; 55 by SPECT/CT

• SPECT/CT reclassified 28/62 foci (45.2%): 5/12 in class 1;

16/29 in class 2; 7/20 in class 3; 1/1 in class 4.

Spinal hardware

infection

Loosening of upper

construct screws without

infection

Bagrosky et al. Pediatr Radiol 2013

[18F]FDG PET/CT in Suspected Infection of

Hardware after Spine Fusion Surgery

Infected spinal hardware

[18F]FDG PET/CT in Suspected Infection of

Hardware after Spine Fusion Surgery

Courtesy of Dr. CJ Palestro, LIJMC, New Hyde Park, NY

[18F]FDG PET/CT in Suspected Infection of

Hardware after Spine Fusion Surgery

Courtesy of Dr. CJ. Palestro, LIJMC, New Hyde Park, NY

Uninfected spinal hardware

Physiologic

al [18F]FDG

distribution

Slightly elevated uptake in the inter- or paraverte-bral region

Clearly elevated uptake with linear or disci-form pattern in the interverte-bral space

Clearly elevated uptake with linear or disciformpattern in the inter-vertebral space and involvement of ground or cover plate or both plates of the adjacent vertebrae

Clearly elevated uptake with linear or disciform pattern in the intervertebral space and involvement of ground or cover plate or both plates of the

adjacent vertebrae +

surrounding soft-tissue

abscess

normal disciti

s

spondylodisciti

s

[18F]FDG in Spinal Infection

Hungenback et al. Nucl Med Commun 2013

Score 2 Score 3

Score 4

[18F]FDG in Spinal Infection

Hungenback et al. Nucl Med Commun 2013

“FDG-PET is a promising alternative to HDP/gallium

imaging because:

- the study is highly sensitive

- the study has high image resolution

-the study is completed in a single session

However, specificity remains an issue because non-

specific accumulation of FDG around the fusion

material is not uncommon and differentiating infection

from tumour will be problematic”

Caveats about [18F]FDG in Spinal Infection

Gemmel et al. Eur J Nucl Med Mol Imaging 2006

At diagnosis After

antibiotic therapy

[18F]FDG PET/CT for Assessing Response to

Therapy in Spinal Infection

Possible threshold in ΔSUVmax change: around 45%

• Kim et al. Prediction of residual disease of

spine infection using F-18 FDG PET/CT.

Spine (Phila Pa 1976) 2009.

• Nanni et al. FDG PET/CT is useful for the

interim evaluation of response to therapy

in patients affected by haematogenous

spondylodiscitis. Eur J Nucl Med Mol

Imaging 2012.

Advantages

• Diagnostic accuracy better than bone/gallium.

• High sensitivity.

• Total-body imaging allows the detection of septic

embolism.

• High negative predictive value.

• Potential for monitoring the efficacy of therapy.

Limitations

• Published evidence: less than a dozen articles with

less than 200 total patients.

• Relatively poor specificity.

• False-positive results possible because of:

- degenerative diseases

- post-surgical inflammatory reaction/recent

fracture

- primary and metastatic spine tumors

Strengths/Weaknesses of [18F]FDG PET for

Spinal Infection

SPECT/CT with 99mTc-HMPAO-WBC:

the Diabetic Foot

99mTc-HMPAO-WBC SPECT/CT: focal accumulation involving both

the soft tissues and the 2rd metatarsal bone (soft tissue infection

and concomitant osteomyelitis).

99mTc-HMPAO-WBC SPECT/CT with 3D fusion Volume Rendering

Diabetes Care 2012; 35: 1826-1831

STAGE 0, INTENSITY

2

SEVERITY INDEX = 2

STAGE III, INTENSITY 3

SEVERITY INDEX =6

STAGE I , INTENSITY 1

SEVERITY INDEX = 2

STAGE 0, INTESITY

1

SEVERITY INDEX =1

COMPOSITE SEVERITY INDEX =

SUM OF SEVRITY INDEX LESIONS/FOOT

CSI =

3

CSI = 8

[18F]FDG PET/CT for Infective Endocarditis

Image interpretation

NEGATIVE for IE POSITIVE for IE

Negative Infection

extra-IE

IE IE+ embolism/

extra-IE

infection

99mTc-HMPAO-WBC scan in patient with “Possible” IE (mechanical

prosthesis of mitral valve). Fever and leukocytosis. Negative TTE

and TEE); blood colture positive for St. Aureus

Labelled WBC for Infective Endocarditis

99mTc-HMPAO-WBC SPECT/CT in patient with “Definite” IE

(positive blood cultures -Pseudomonas- and fever few months

after implant of mitral valve mechanical prosthesis). Clear focus

of uptake in right heart, that SPECT/CT identifies as endocarditis

of the native tricuspid valve. Endocarditis of mechanical

prosthesis, expected site of infection was thus excluded.

Labelled WBC for Infective Endocarditis

65 yr old man with previous IE after kidney

transplantation; occasional finding of vegetation at

the mitral valve. No fever, normal WBC.

Baseline

May 2007

After ABT

October 2007

Pocket EC Pocket + EC

Image interpretation

Pocket Infection

Infection EC intravascular

99mTc-HMPAO-WBC SPECT/CT

Infection of the intracardiac portion of the lead

Advantages:

• High sensitivity.

• Whole-body images allow the detection of septic embolism.

• High negative predictive value.

Limitations:

• Relatively poor specificity.

• Chance of high uptake of myocardial tissue.

• False-positive results possible because of:

- recent thrombi

- soft atherosclerotic plaques

- primary and metastatic cardiac tumors

- sarcoidosis

- post-surgical inflammatory reaction

- artifacts

Diagnostic Performance of [18F]FDG PET/CT for IE

Advantages:

• Discrimination between septic and sterile vegetations

detected at echocardiography.

• Whole-body images followed by additional planar and

SPECT/CT spot images allow the detection of distant

sites of septic embolism.

Limitations:

• False-negative results possible because of:

- small vegetations (< 5 mm)

- mycetes and infections with low leukocyte

recruitment

- long-lasting antibiotic treatment

- warning for very early post-surgical IE

Diagnostic Performance of Labelled WBC for IE

Millar BC et al, Int J Cardiol (2013)

Classification of Vascular Prosthesis

Infections (VPI)

Time from procedure to infection:

• Early (acute): < 4 months (+++ first 2 months)

• Subacute: 4-12 months

• Late (chronic): > 12 months (“biofilm”)

• Scintigraphy with radiolabelled WBC

(99mTc o 111In) is most frequently used.

• Pre-hybrid imaging meta-analysis:99mTc-HMPAO-WBC sensitivity: 82-100%

specificity 85-100%

versus 75% sensitivity 75and 56.6% specificity

for CT

SPECT/CT:

reduces FP

defines extent of disease

facilitates imaging reading even when post-surgical changes are present

high specificity even if performed early post-surgery

high sensitivity for late VPI

30 min

4 ore

[18F]FDG-PET/CT for VPI Assessment:

Sensitivity = 93% (versus 64% for CT)

Specificity = 70-91% (versus 86% for CT)

increased accuracy when the criteria of

FOCAL [18F]FDG uptake + irregular border of

the prosthesis are adopted

Diffuse uptake = inflammation, post-surgical

scar that can persist for years after surgery

(heterologous material)

Focal [18F]FDG + irregular prosthesis

border can predict the presence of VPI

with <5% diagnostic error

Spacek et al. Eur J Nucl Med Mol Imaging. 2009

• 99mTc-HMPAO WBC “gold standard” for diagnosis of VPI

• diagnostic accuracy increases by using SPECT/TC

• [18F]FDG-PET/CT with specific interpretation criteria is good option

1. High clinical suspicion and negative CT.

2. Lack of clinical response after adequate

antibiotic therapy.

3. Monitoring treatment response?

When and Why?

1. Clinical suspicion wih

unconclusive diagnostic angio-

CT

2. Lack of clinical response after

adequate ABT

3. Monitoring treatment response? [18F]FDG

Labeled

WBC

Labeled

WBC

Which Radiopharmaceutical?

[18F]FDG

High NPV