pet and spect in infection and inflammation...pet and spect in infection and inflammation mike...
TRANSCRIPT
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