PET and SPECT in Infection and Inflammation

Mike Sathekge, MD, PhD

President: ISORBE

HOD: Nuclear Medicine, University of Pretoria

IPET 2015 IAEA, Vienna

Rugby World Cup 2015

South Africa 64 - 0 USA

Acknowledgements ISORBE IAEA Ora Israel Chris Palestro Guiliano Mariani Alex Maes Christophe vd Wiele Andor Glaudemans Alberto Signore Dept of Nuclear Medicine: UP & SBAH

Molecular Imaging

Infective Endocartis

TB & HIV Next Talk

FOU

DM & Osteomyletis

Graft Infection

Prosthetic Infection

Infection

Molecular Imaging

Inflammatory Bowel Disease

Cardiac Sarcoid 2016

Reumatoid Athritis

Vasculitis

Polymyalgia Rheumatica

Sarcoidosis

Inflammation

Infection not Synonymous with Inflammation

Infection / inflammation is still a major cause of morbidity and mortality despite advances in both diagnosis and treatment Inflammation: – The complex biologic response of tissues to harmful

stimuli

Infection: – A detrimental colonization by a foreign species

(pathogen) in which the host provides the resources necessary for the infecting species to multiply

Examples: bacteria, virus, parasites, fungi, prions, etc

Fever of Unknown Origin (FUO) Fever >38.3ºC, >3 weeks duration Incidence: 7-53% (geographic factors, definition) Final diagnosis: Infection, 25-30% of cases Neoplasms, ~10% of cases

– mainly: lymphoma, leukemia, renal cell, liver mets Aseptic inflammatory processes

– collagen, vascular, granulomatous diseases Miscellaneous

– e.g.drug-induced fever, CVA, thrombo-embolic processes

Recent: decrease in patients with final etiology Functional imaging approach: WBC, Ga-67, FDG

FDG PE/CT IMAGING IN FUO

Sathekge et al, Clin Nucl Med 2015

Bleeker-Rovers et al , EJNMI 2007

Kouijzer et al, Sem Nucl Med 2013

Sarcoidosis Rheumatic Fever Cutaneous T Lymphoma

FDG PET/CT: FUO

High Negative Predictive Value

High Sensitivity, contributes in >1/3 of cases

Imaging modality of choice for FUO

Helpful in immunocompromised/neutropenic patients

Infective Endocarditis

Diagnosis of IE is challenging because of several factors: - indiscriminate use of antimicrobial agents early during febrile episodes; - predisposing/underlying conditions (frail and elderly, immunosuppressed persons, i.v. drug abuse); - increasing number of interventional cardiovascular procedures and placement of valve prostheses, intra- vascular devices, and/or cardiac devices.

Incidence of infectious endocarditis (IE): 2-4 new cases/100,000 per year.

Erba, Mariani et al. JNM 2012

High mortality if undiagnosed and not treated

99mTc-HMPAO-WBC SPECT/CT images in patient with positive blood cultures and fever that arose a few months after implant of mechanical mitral valve prosthesis. SPECT images show clear focus of accumulation in right heart, that SPECT/CT identifies as endocarditis of the native tricuspid valve. Endocarditis of mechanical prosthesis, expected site of infection before 99mTc-HMPAO-WBC SPECT/CT was performed, was thus excluded.

Saby et al. Journal of the American College of Cardiology, 2013

FDG PET/CT in Prosthetic Valve Endocarditis (PVE)

Modified PET/CT Duke Criteria

Positive 18F-FDG PET/CT: abnormal FDG uptake at the site of prosthetic valve

Saby et al. Journal of the American College of Cardiology, 2013

FDG PET/CT in Prosthetic Valve Endocarditis (PVE)

FDG PET/CT in Prosthetic Valve Endocarditis (PVE)

Early diagnosis, especially in negative echocardiography • echocardiography is normal or inconclusive in almost 30%, leading to a decreased diagnostic accuracy for the modified Duke criteria

FDG not a substitute for clinical, microbiological, and echo

FDG PET/CT novel major Duke criterion & Dx Algorythm

Whole-body imaging: useful for detecting emboli, metastatic infection, even neoplastic lesions

Potential to monitor response to antimicrobial treatment

The Diabetic Foot Peripheral neuropathy is common in DM 5-10% lead to foot ulceration ± bone destruction ~ 10% hospitalization expenses in diabetics

Osteomyelitis occurs in up to 1/3 of diabetic foot infections direct spread from contaminated soft tissue diagnosis [early]: challenging but crucial X-rays, CT, MRI, bone scan: high sensitivity & low

specificity (s/a amputation, fractures, osteoarthritis) WBC scintigraphy

18F-FDG PET/CT REPLACE WBC IMAGING IN THE DIABETIC FOOT?

18F-FDG PET/CT was found to have a low diagnostic accuracy in the diabetic foot. No useful SUVmax criteria for differentiating between soft-tissue infection and osteomyelitis could be found. WBC scintigraphy is more accurate WBC scintigraphy currently remains the gold standard imaging technique. Predisposing: Vascular insufficiency Neuropathy Immune response impairment

Familiari et al, J Nucl Med 2011 Keidar & Israel et al, J Nucl Med 2014

Kagna et al, EJNMMI 2012 Palestro & Love. Semin Nucl Med 2009

Diabetic foot blood glucose - 190 mg/dl TP study

Diabetic patient, vascular graft blood glucose - 84 mg/dl FN study

Osteomyelitis 4th metatarsus Infected surgical wound

FDG, Infection, Diabetes & Hyperglycemia Specific Considerations

Diabetes mellitus: incidence 7-8% in western countries (up to18% > 65y) Hyperglycemia occurs frequently after administration of steroids [or chemotherapy]

Ora Israel

Vascular Graft Infection Incidence: 0.5-5% , severe complication – Infra-inguinal 2-5% – Aortofemoral 1-2% – Aortic grafts 1%

≥ 4 months following surgery Early, accurate diagnosis: challenging and of utmost clinical significance for further management Delay in treatment : severe complications, e.g. sepsis, haemorrhage, amputation Main successful therapeutic option: surgery for removal of infected graft - major procedure with high morbidity (eradication is rarely possible after graft is infected) Poor prognosis: related to anatomical site (aortic), may result in life or limb loss (>50% of patients)

Israel et al, IAEA, Workshop 2011

Infected vs. Non-Infected Grafts

Confirmed at surgery - infected graft removed

Keidar et al, J Nucl Med 2007

Soft tissue infection without graft involvement

Differentiating Infected vs. Non-Infected Prosthetic Vascular Grafts

• High intensity, focal & irregular boundaries • Point scale: a=5, b=3, c=4 • SUV max >8 lesion

Saleem et al, BioMed Res Int 2014

Diffuse uptake in 92% of noninfected vascular prostheses (higher in Dacron grafts)

Intensity of uptake in synthetic grafts does not change over time.(can be sustained for 16yrs)

Pitfalls: Noninfected vascular prosthesis

Keidar & Israel et al, J Nucl Med 2014

Diffuse: Gore-Tex

Inhomogenous: Dacron

SUVmean of 2.5

SUVmean of 1.1

Pattern: • Diffuse & linear • Can be inhomogenous • Can persist for yrs (16)

Hypothesis: Chronic aseptic inflammatory process related to the graft material, mediated by macrophages, fibroblasts, and giant cells.

Wasselius et al, J Nucl Med 2007 Keidar & Israel et al, J Nucl Med 2014

Non-infected Grafts

INFECTED PROSTHESIS

Risk of infection in 1-4% of first replacement 10% of lower limb arthroplasties need surgical revision, of which 70 % are due to loosening; risk of infection in up to 30% of pts 111 In oxin or 99m Tc HMPAO labeled leukocyte scanning in combination with Tc-sulfur colloid marrow imaging: accuracy > 95% in hip and knee Why need for other techniques?: – Separating, labeling and re-injection of patient’s white blood cells – Complex, time consuming – Delayed imaging after 24 h

Aseptic Loosening vs. Infection

Aseptic Loosening Histiocytes Giant cells

Lymphocytes Plasma cells

Infection Histiocytes Giant cells

Lymphocytes Plasma cells Neutrophils

Bone/Gallium Scintigraphy

Infected Rt. THR

Aseptically Loosened Rt. THR

Labeled Leukocyte Imaging In-vitro labeling

111In-oxine 99mTc-exametazime

Uptake mechanisms Intact chemotaxis

Number of cells labeled (≥ 2000/mL)

Cell types labeled (neutrophils) Cellular inflammatory response (neutrophilic) Performed in conjunction with bone marrow

imaging (99mTc sulfur colloid)

Principle of Leukocyte/Marrow Imaging

Leukocytes and sulfur colloid both accumulate in marrow

Infection ↑ Leukocyte uptake ↓ Sulfur colloid uptake

Image interpretation Activity on labeled leukocyte image without corresponding activity on marrow image = osteomyelitis

BONE and WHITE BLOOD CELL SCINTIGRAPHY IN INFECTED HIP PROSTHESIS

BONE scintigraphy white blood cell after 4h white blood cell after 24h

Which THR is Infected?

111In-WBC 99mTc-SC

1

2

Lt. THR

Rt. THR

Palestro . ISORBE 2014

# 1 is Infected

111In-WBC 99mTc-SC

1

2

Lt. THR

Rt. THR

Prosthesis Sensitivity Specificity Accuracy Bone All (150) 52/67 (.78) 31/83 (.37) 83/150 (.55)

THR (94) 20/34 (.59) 30/60 (.50) 50/94 (.53)

TKR (56) 32/33 (.97) 1/23 (.04) 33/56 (.59)

Bo/Ga All (150) 51/67 (.76) 49/83 (.59) 100/150 (.67)

THR (94) 21/34 (.62) 42/60 (.70) 63/94 (.67)

TKR (56) 30/33 (.91) 7/23 (.30) 37/56 (.66)

WBC/Ma All (150) 64/67 (.95) 72/83 (.87) 136/150 (.91)

THR (94) 32/34 (.94) 53/60 (.88) 85/94 (.90)

TKR (56) 32/33 (.97) 19/23 (.83) 51/56 (.91)

Leukocyte/Marrow Scintigraphy in Joint Replacement Infection*

Love et al, SNM 2008

Accumulation of labelled WBC in infection sites is a dynamic process

Glaudemans al, 2013

Glaudemans & Signore Erba et al, EJNMMI 2014

Sensitivity Specificity PPV NPV Accuracy

SPECT/CT 99.0 94.5 92.5 98.5 94.5 Planar/SPECT

95 74.3 84.6 91.3 86.9

99mTc-UBI 29-41 SPECT/CT

O Garcia, Estrada, Sathekge et al, 2015

184 consecutive patients with suspected infection

• False positives related to high vascularizated tumors • False negatives for low labeling quality. • No differentiation (with imaging) of different pathogens. • Not useful in detection of intracellular pathogens.

Ostovar A, Assadi M, Vahdat K, et.al. “A pooled analysis of diagnostic value of 99m Tc-ubiquicidin (UBI) scintigraphy in detection of an infectious process”, Clin Nucl Med 2013; 38(6):413-416. Saeed A, Babar M, Afzal M, et. al. “Review article: Antimicrobial peptides as infection imaging agents: Better than radiolabeled antibiotics”, Hindawi Publishing Corporation, International Journal of Peptides, 2012.

LIMITATIONS OF UBIQUICIDINE LIMITATIONS OF UBI

PreTherapy 1 month after Rx

Response to therapy

E Estrada, O Garcia. WFNMB 2014.

Infected vs Noninfected Prosthesis

Alavi & Zhuang

Prosthetic Joint

Primary role of Nuclear Medicine Identify the infected prosthetic joint

Radionuclide gold standard

Labeled leukocyte/marrow imaging

18F-FDG not useful for diagnosing prosthetic joint infection

FDG in Spinal Osteomyelitis Author N= Sens Spec Acc Guhlman JNM (1998)

4 3/3 1/1 4/4

Kalicke EJNM (2000)

7 7/7 NA NA

Meller EJNM (2002)

9 4/4 5/5 9/9

Gratz EJNM (2002)

16 12/12 3/4 15/16

Stumpe AJR (2002)

38 5/5 33/33 38/38

deWinter Spine (2003)

57 15/15 100%

34/42 81%

49/57 86%

Asymptomatic Bilateral L5 Pars Interarticularis Defects

← ← →

Facet Arthritis

Palestro, Semin Nucl Med 2013

[18F]FDG PET in POSI

5-point scale proposed for [18F]FDG uptake:

0 = no uptake 1 = uptake < blood pool 2 = uptake ≈ blood pool 3 = uptake < liver but > blood pool 4 = uptake > liver

3-point scale: location of uptake:

1 = uptake adjacent to ROI 2 = uptake in ROI 3 = uptake in ROI & adjacent to ROI

FDG & Spinal Osteomyelitis • MRI is the imaging modality of choice • Infection: body & intervertebral (posterior elements in 20%)

• Accuracy comparable to 67Ga

• High negative predictive value Useful for distinguishing infection

from severe degenerative changes

• Specificity may be adversely affected by Spinal implants

Coexistent tumor Recent fracture Degenerative changes

Palestro, Semin Nucl Med 2013 & 2015

FDG PET/CT: Fungal Infection

• Neutropenic leukemia patient with aspergillosis infection. • FDG demonstrate incomplete remission – continuation with antifungal treatment

Glaudemans et al,Clin & Dev Immun2013

In patients who are taking antibiotics for a long time period, Immune-suppresed; HIV, Steroid, Chemo

Antifungal therapy is extensive and must be prolonged for a long time, sometimes even for months.

FDGPET/CT could help to decide whether therapy should be continued, stopped, or switched (monitoring of therapy efficacy)

Vasculitis Inflammatory process with leucocyte infiltration in, and reactive damage to the vascular wall. Vascular wall thickening progressing to fibrosis

Diagnosis: biopsy. FDG-PET/CT: –Pattern: diffuse increased FDG uptake along vascular walls in large vessels (Giant cell, Takayasu) –Mechanism: FDG uptake in smooth muscle proliferation and/or in macrophages

Effective in diagnosis, assessing extent of disease & monitoring response to treatment

Routine use of is still delayed

[18F]FDG PET in Large-Vessel Vasculitis

Four-point scale proposed for [18F]FDG uptake:

Grade 0 = no uptake Grade 1 = minimal uptake (< liver) Grade 2 = moderate uptake (≈ liver) Grade 3 = marked uptake (> liver)

Meller J et al. Eur J Nucl Med Mol Imaging 2003

Grade 0 Grade 2 Grade 3

GCA & PMR Large vessels (aorta, subclavian, carotid, iliac,femoral) accompanied by: Large joints

Takayasu’s arteritis: more centrally (aorta and main branches in the thoracic region)

Polyarteritis nodosa and polychondritis: medium- and small-sized (best visible in the legs) accompanied by: nose, the ears, and the costochondral regions.

Vasculitis

Glaudemans et al,Clin Dev Immun 2013

[18F]FDG-PET in Large-Vessel Vasculitis: Conclusions

Diagnosis and follow-up (better sensitivity & specificity)

Assessing Disease activity and extent

Target site for biopsy

Guiding treatment strategy and evaluating therapy response

Granulomatous non-caseating disease Unknown etiology Multisystem, preferentially intrathoracic and upper respiratory tract Staging – Clin, CXR,CT,Lung test, ACE, ANCA, Ga67 – Endoscopy of rhinopharynx, pharynx, larynx and bronchy

PET/CT: Sarcoidosis

Braun, EJNM 2008

FDG-PET Ga 67

Nishiyama et al,JNM 2006

Classification of Sarcoidosis Type I: thoracic lymph node involvement

Type II: involvement of the lung parenchyma

Type III: diffuse lymph node involvement

Type IV: organ involvement

• SUVmax correlates with histopathological results from bronchoalveolar lavage

• Diffuse parenchymal uptake predicts a future deterioration

Prognosis and stratification: parenchymal disease, splenomegaly, and involvement of more than three organ systems is associated with a poor prognosis

Glaudemans et al,Clin & Dev Immun2013 Keijsers et al,EJNMMI 2010

Braun, EJNM 2008

Baseline 3 months after CS treatment:

Progression

3 months after CS & Methotrexate

Remission

Glaudemans et al,Clin & Dev Immun2013

Therapy Response: Sarcoidosis

• 18F-FDG PET is a unique imaging technique that can assess the metabolic activity of synovitis and measure the disease activity in RA. • Corresponds well with clinical and ultrasound joints assessment • Further studies are of course needed before 18F-FDG PET analysis of RA joints can be considered as an established method for diagnosis and therapeutic follow-up in rheumatology practice. Beckers et al, Journal of Nuclear Medicine 2004 Jun; 45 (6): 956-964

18F-FDG PET images of • healthy control subject (A and B) • RA patient with active disease (C and D)

FDG PET/CT: Reumatoid Arthritis Need for more evidence

IBD CROHN'S

DISEASE (CD) Affects from the

mouth to the anus discontinous

Distal small bowel and terminal ileum

ULCERATIVE COLITIS (UC) Affects the colon Rectum

Chronic disease with abdominal symptoms

such as diarrhea, abdominal pain and

bloody stools

Complications:

Fulminant colitis, strictures, fistulas, abscesses, cancer

INAPPROPRIATE INFLAMMATORY RESPONSE TO INTESTINAL MICROBES IN A GENETICALLY SUSCEPTIBLE HOST

Idiopathic Inflammatory Bowel Disease

Noriega & Martin-Comin, ISORBE 2015

UC CD Anterior abdomen + caudo-cranial (sitting) views 99mTc-WBC: 30-60 min and <3 h p.i. SPECT/CT: in late/second imaging Scintigraphic activity index(SAI): Extent & Severity PET: Promising

Male, 35 y, UC corticoidresistant Fever, intense abdominal pain Mucous diarrhea (>6/day) Leukocytes: 7600; CRP: 85,6 mg/L (<5); ESR:30 Coproculture: negative Treat.: CyA, AZA, PDN 10490805

SAI 19 04/11

SAI 7 11/12

2: Different ways of reading the scans

Why many probes not suitable as bacteria-specific infection imaging agents

3: Differences in the performance of the labeling procedure leading to formation of different complexes

1: Inability of the compound to discriminate infection from sterile inflammation

4: Insufficient quality control

These limitations have been largely overcome by the hybrid PET/CT and SPECT/CT technology O Israel & Z Keidar, Annals of the New York Academy of Sciences 2011

99mTc-DTPA-bis(INH) which has shown great potential in imaging extrapulmonary TB infections.

Infection Specific: 1. Does not accumulate in bone marrow 2. Theoretically it should not accumulate in the inflammed focii

99mTc-ciprofloxacin

Monitoring Response: Promising

Clinical evaluation: (Aktar MS et al. Int J Peptide 2012) 1. Mixed Results (Sens=85.4%, Spec=81.7%.) 2. Excellent for identification of bone, joint & soft tissue infection

Rationale/mechanism: Broad spectrum quinolone-binds to the DNA gyrase of bacteria & inhibit DNA synthesis

99mTc-ciprofloxacin SPECT/CT

Baseline study Follow-up after 16 wks

Victoria E. Soroa

2: Insufficient numbers of viable intralesional bacteria

Contradictions: Possible explanations

3: Nonspecific binding to dead intralesional bacteria

4: Use antibiotic therapy before imaging

1: Presence of ciprofloxacin-resistant bacteria

5: Binding to mammalian DNA abundantly present in infiltrating leukocytes

Single-step 111In-biotin Scintigraphy In Spinal Infection

Sensitivity Specificity

Accuracy PPV NPV

Preoperative spondylodiscitis

84% 98% 92% 96% 90%

Postoperative spondylodiscitis

100% 84% 92% 87% 100%

Lazzeri et al. 110 patients prospectively evaluated for suspected spinal infection 71 patients suspected to have preoperative spondylodiscitis (group 1) 39 patients suspected to have postsurgical infection (group 2)

Scintigraphic imaging of vertebral osteomyelitis with 111in-biotin. Lazzeri E, Erba P, Perri M, Tascini C, Doria R, Giorgetti J, Mariani G. Spine (Phila Pa 1976). 2008 Apr 1;33(7):E198-204.

Sensitivity Specificity PPV NPV Accuracy

SPECT/CT 99.0 94.5 92.5 98.5 94.5 Planar/SPECT

95 74.3 84.6 91.3 86.9

99mTc-UBI 29-41 SPECT/CT

O Garcia, Estrada, Sathekge et al, 2015

184 consecutive patients with suspected infection

Tracer Classification Published 68Ga-DOTA-VAP-P1 Peptide Ujula et al. 2009

68Ga-DOTA-Siglec-9 Peptide Ahtinen et al. 2014

68Ga-NOTA-UBI Antimicrobial peptide Ebenhan et al. 2011

68Ga-TF Apo-transferrin Kumar et al. 2011

68Ga-TAFC, -FOXE Siderophores Petrik et al. 2010

68Ga-CITRATE Citrate (citric acid)

Hnatowich DJ, 1975

Kumar et al. 2009

Rizello et al. 2010

Nanni et al. 2009

Vorster et al .2014

68Ga(3+) Gallium(III)chloride Maekinen et al. 2005

68Ga-candidates for infection imaging

7 days 24 hrs

Infection

Healing

Infection Specific: 1. Bone infection(S. aures) from surgery in 7 days post-op 2. Inflammation associated with atherosclerotic plaques 3. Visualise inflammation better than tumour

Findings about 68Ga-DOTAVAP-P1

Monitoring Response: Can determine the phase and rate of infection

Clinical evaluation: Not as yet

Rationale/mechanism: Endothelial glycoprotein – recruitment of recruiting leucocytes/CD8 into sites of inflammation

Why cationic antimicrobial peptides?

Why [68Ga]NOTA- Ubiquicidin (UBI 1-59)?

Positive prognosis (UBI-Fragments such as 29-41 are specific &

sensitive towards infection)

68Gallium half life matches most peptide’s

pharmacology

Straightforward radiolabeling expected

“shake and shoot””

Non-toxic with no side effects

NOTA is more 68Gallium specific

than DOTA

Sathekge, Nucl Med Commun 2008, 26:663-65

Interesting Developments Are Ongoing

Potential: 1. Tracers that are well investigated 2. First-in-human data is available 3. Can be easily introduced in the clinic (SPECT/CT & PET/CT)

Clinical evaluation: 99mTc-ciprofloxacin 99mTc-UBI (29-41) 68Ga-DOTAVAP-P1 68Ga-Citrate 68Ga-UBI (29-41)

Many tracers still do not fulfill the expectation. Good comparative studies are lacking; it is difficult to support one approach over the other.

Conclusion

Help resolve the: pathogenesis complex interplay between: inflammatory, and infections: PET/CT (new tracers?)

High sensitivity and high negative predictive value (Diagnostic criteria is crucial).

PETCT: Therapy response assessment, patient-specific effect on outcome, likely image-based “biomarker”

Transdisciplinary research using of multi-imaging modality imaging approaches

Growth enhanced by novel targeted molecular imaging probes, developed and tested in the small-animal imaging environment