PET and SPECT in Infection and Inflammation

Transcription

1 PET and SPECT in Infection and Inflammation Mike Sathekge, MD, PhD President: ISORBE HOD: Nuclear Medicine, University of Pretoria IPET 2015 IAEA, Vienna

2 Rugby World Cup 2015 South Africa 64-0 USA

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

4 Molecular Imaging TB & HIV Next Talk Infective Endocartis DM & Osteomyletis Infection FOU Graft Infection Prosthetic Infection

5 Molecular Imaging Cardiac Sarcoid 2016 Inflammatory Bowel Disease Vasculitis Inflammation Reumatoid Athritis Polymyalgia Rheumatica Sarcoidosis

6 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

7 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

8 FDG PE/CT IMAGING IN FUO Sarcoidosis Rheumatic Fever Cutaneous T Lymphoma Sathekge et al, Clin Nucl Med 2015 Bleeker-Rovers et al, EJNMI 2007 Kouijzer et al, Sem Nucl Med 2013

9 FDG PET/CT: FUO High Negative Predictive Value High Sensitivity, contributes in >1/3 of cases Helpful in immunocompromised/neutropenic patients Imaging modality of choice for FUO

10 Infective Endocarditis Incidence of infectious endocarditis (IE): 2-4 new cases/100,000 per year. 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, intravascular devices, and/or cardiac devices. High mortality if undiagnosed and not treated Erba, Mariani et al. JNM 2012

11 99m Tc-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 99m Tc-HMPAO-WBC SPECT/CT was performed, was thus excluded.

12 FDG PET/CT in Prosthetic Valve Endocarditis (PVE) Saby et al. Journal of the American College of Cardiology, 2013

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

14 FDG PET/CT in Prosthetic Valve Endocarditis (PVE) Saby et al. Journal of the American College of Cardiology, 2013

15 FDG PET/CT in Prosthetic Valve Endocarditis (PVE) FDG not a substitute for clinical, microbiological, and echo 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 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

16 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

17 18 F-FDG PET/CT REPLACE WBC IMAGING IN THE DIABETIC FOOT? 18 F-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 Kagna et al, EJNMMI 2012 Palestro & Love. Semin Nucl Med 2009 Familiari et al, J Nucl Med 2011 Keidar & Israel et al, J Nucl Med 2014

18 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] Diabetic foot blood glucose mg/dl TP study Diabetic patient, vascular graft blood glucose - 84 mg/dl FN study Osteomyelitis 4 th metatarsus Infected surgical wound Ora Israel

19 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

20 Infected vs. Non-Infected Grafts Confirmed at surgery - infected graft removed Soft tissue infection without graft involvement Keidar et al, J Nucl Med 2007

21 Differentiating Infected vs. Non-Infected Prosthetic Vascular Grafts Saleem et al, BioMed Res Int 2014 High intensity, focal & irregular boundaries Point scale: a=5, b=3, c=4 SUV max >8 lesion

22 Pitfalls: Noninfected vascular prosthesis 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) Keidar & Israel et al, J Nucl Med 2014

23 Diffuse: Gore-Tex Non-infected Grafts Pattern: Diffuse & linear Can be inhomogenous Can persist for yrs (16) SUVmean of 1.1 Inhomogenous: Dacron Hypothesis: Chronic aseptic inflammatory process related to the graft material, mediated by macrophages, fibroblasts, and giant cells. SUVmean of 2.5 Keidar & Israel et al, J Nucl Med 2014 Wasselius et al, J Nucl Med 2007

24 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

25 Aseptic Loosening vs. Infection Aseptic Loosening Histiocytes Giant cells Lymphocytes Plasma cells Infection Histiocytes Giant cells Lymphocytes Plasma cells Neutrophils

26 Bone/Gallium Scintigraphy Infected Rt. THR Aseptically Loosened Rt. THR

27 Labeled Leukocyte Imaging In-vitro labeling 111 In-oxine 99m Tc-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 ( 99m Tc sulfur colloid)

28 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

29 BONE and WHITE BLOOD CELL SCINTIGRAPHY IN INFECTED HIP PROSTHESIS BONE scintigraphy white blood cell after 4h white blood cell after 24h

30 Which THR is Infected? Lt. THR 1 Rt. THR 2 Palestro. ISORBE In-WBC 99m Tc-SC

31 # 1 is Infected Lt. THR 1 Rt. THR In-WBC 99m Tc-SC

32 Leukocyte/Marrow Scintigraphy in Joint Replacement Infection* 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) Love et al, SNM 2008

33 Accumulation of labelled WBC in infection sites is a dynamic process Glaudemans al, 2013

34 Glaudemans & Signore Erba et al, EJNMMI 2014

35 99m Tc-UBI SPECT/CT 184 consecutive patients with suspected infection Sensitivity Specificity PPV NPV Accuracy SPECT/CT Planar/SPEC T O Garcia, Estrada, Sathekge et al, 2015

36 LIMITATIONS OF UBIQUICIDINE LIMITATIONS OF UBI 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): 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.

37 E Estrada, O Garcia. WFNMB Response to therapy PreTherapy 1 month after Rx

38 Infected vs Noninfected Prosthesis Alavi & Zhuang

39 Prosthetic Joint Primary role of Nuclear Medicine Identify the infected prosthetic joint Radionuclide gold standard Labeled leukocyte/marrow imaging 18 F-FDG not useful for diagnosing prosthetic joint infection

40 FDG in Spinal Osteomyelitis Author N= Sens Spec Acc Guhlman JNM (1998) Kalicke EJNM (2000) Meller 4 3/3 1/1 4/4 7 7/7 NA NA 9 4/4 5/5 9/9 EJNM (2002) Gratz EJNM (2002) Stumpe AJR (2002) dewinter Spine (2003) 16 12/12 3/4 15/ /5 33/33 38/ /15 34/42 49/57 100% 81% 86%

41 Asymptomatic Bilateral L5 Pars Interarticularis Defects Facet Arthritis Palestro, Semin Nucl Med 2013

42 [ 18 F]FDG PET in POSI 3-point scale: location of uptake: 1 = uptake adjacent to ROI 2 = uptake in ROI 3 = uptake in ROI & adjacent to ROI 5-point scale proposed for [ 18 F]FDG uptake: 0 = no uptake 1 = uptake < blood pool 2 = uptake blood pool 3 = uptake < liver but > blood pool 4 = uptake > liver

43 FDG & Spinal Osteomyelitis MRI is the imaging modality of choice Infection: body & intervertebral (posterior elements in 20%) Accuracy comparable to 67 Ga 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

44 FDG PET/CT: Fungal Infection 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) Neutropenic leukemia patient with aspergillosis infection. FDG demonstrate incomplete remission continuation with antifungal treatment Glaudemans et al,clin & Dev Immun2013

45 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

46 [ 18 F]FDG PET in Large-Vessel Vasculitis Four-point scale proposed for [ 18 F]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

47 Grade 0 Grade 2 Grade 3

48 Vasculitis 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) Glaudemans et al,clin Dev Immun 2013 Polyarteritis nodosa and polychondritis: medium- and small-sized (best visible in the legs) accompanied by: nose, the ears, and the costochondral regions.

49 [ 18 F]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

50 PET/CT: Sarcoidosis 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 Ga 67 FDG-PET Braun, EJNM 2008 Nishiyama et al,jnm 2006

51 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

52 Therapy Response: Sarcoidosis Baseline 3 months after CS treatment: Progression 3 months after CS & Methotrexate Remission Glaudemans et al,clin & Dev Immun2013 Braun, EJNM 2008

53 FDG PET/CT: Reumatoid Arthritis Need for more evidence 18F-FDG PET images of healthy control subject (A and B) RA patient with active disease (C and D) 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):

54 Idiopathic Inflammatory Bowel Disease 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 Complication s: Fulminant colitis, strictures, fistulas, abscesses, cancer INAPPROPRIATE INFLAMMATORY RESPONSE TO INTESTINAL MICROBES IN A GENETICALLY SUSCEPTIBLE HOST Noriega & Martin-Comin, ISORBE 2015

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

56 SAI 19 04/11 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 /12 SAI 7

57 Why many probes not suitable as bacteria-specific infection imaging agents 1: Inability of the compound to discriminate infection from sterile inflammation 2: Different ways of reading the scans 3: Differences in the performance of the labeling procedure leading to formation of different complexes 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

58 99m Tc-DTPA-bis(INH) which has shown great potential in imaging extrapulmonary TB infections.

59 99m Tc-ciprofloxacin Rationale/mechanism: Broad spectrum quinolone-binds to the DNA gyrase of bacteria & inhibit DNA synthesis Infection Specific: 1. Does not accumulate in bone marrow 2. Theoretically it should not accumulate in the inflammed focii 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

60 99m Tc-ciprofloxacin SPECT/CT Baseline study Follow-up after 16 wks Victoria E. Soroa

61 Contradictions: Possible explanations 1: Presence of ciprofloxacin-resistant bacteria 2: Insufficient numbers of viable intralesional bacteria 3: Nonspecific binding to dead intralesional bacteria 4: Use antibiotic therapy before imaging 5: Binding to mammalian DNA abundantly present in infiltrating leukocytes

62 Single-step 111 In-biotin Scintigraphy In Spinal Infection 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) Preoperative spondylodiscitis Postoperative spondylodiscitis Sensitivity Specificit y Accuracy PPV NPV 84% 98% 92% 96% 90% 100% 84% 92% 87% 100% 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) Apr 1;33(7):E

63 99m Tc-UBI SPECT/CT 184 consecutive patients with suspected infection Sensitivity Specificity PPV NPV Accuracy SPECT/CT Planar/SPEC T O Garcia, Estrada, Sathekge et al, 2015

64 68 Ga-candidates for infection imaging Tracer Classification Published 68 Ga-DOTA-VAP-P1 Peptide Ujula et al Ga-DOTA-Siglec-9 Peptide Ahtinen et al Ga-NOTA-UBI Antimicrobial peptide Ebenhan et al Ga-TF Apo-transferrin Kumar et al Ga-TAFC, -FOXE Siderophores Petrik et al Hnatowich DJ, 1975 Kumar et al Ga-CITRATE Citrate (citric acid) Rizello et al Nanni et al Vorster et al Ga(3+) Gallium(III)chloride Maekinen et al. 2005

65 24 hrs 7 days Infection Healing

66 Findings about 68Ga-DOTAVAP-P1 Rationale/mechanism: Endothelial glycoprotein recruitment of recruiting leucocytes/cd8 into sites of inflammation 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 Monitoring Response: Can determine the phase and rate of infection Clinical evaluation: Not as yet

67 Why cationic antimicrobial peptides? 68 Gallium half life matches most peptide s pharmacology Straightforward radiolabeling expected shake and shoot Non-toxic with no side effects Positive prognosis (UBI-Fragments such as are specific & sensitive towards infection) Why [ 68 Ga]NOTA- Ubiquicidin (UBI 1-59)? NOTA is more 68 Gallium specific than DOTA Sathekge, Nucl Med Commun 2008, 26:663-65

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70 Interesting Developments Are Ongoing Many tracers still do not fulfill the expectation. Good comparative studies are lacking; it is difficult to support one approach over the other. 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: 99m Tc-ciprofloxacin 99m Tc-UBI (29-41) 68 Ga-DOTAVAP-P1 68 Ga-Citrate 68 Ga-UBI (29-41)

71 Conclusion High sensitivity and high negative predictive value (Diagnostic criteria is crucial). Help resolve the: pathogenesis complex interplay between: inflammatory, and infections: PET/CT (new tracers?) 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