18F-FDG PET for Diagnosing Infections in Prosthetic Joints

      Keywords

      Key points

      • The diagnostic performance of fludeoxyglucose F 18 (18F-FDG) positron emission tomography (PET) in detecting periprosthetic joint infection (PJI) in hip and knee replacements seems sufficiently high for routine clinical application and adds to conventional tests in terms of diagnostic accuracy.
      • Iterative metal artifact reduction of computed tomography data improves PET image quality around prostheses.
      • Location rather than intensity of 18F-FDG uptake is critical in diagnosing hip and knee PJI.
      • 18F-FDG uptake at the middle portion of the femoral shaft at the bone-prosthesis interface is highly suspicious for hip PJI.
      • 18F-FDG uptake at the bone-prosthesis interface has been consistently reported as diagnostic criterion for knee PJI.

      Introduction

      In 2010, a little more than 2% of the US population were living with a hip or total knee replacement, which corresponds to approximately 7 million people.
      • Maradit Kremers H.
      • Larson D.R.
      • Crowson C.S.
      • et al.
      Prevalence of total hip and knee replacement in the United States.
      Given the increasing number of individuals who choose elective joint replacements to maintain active lifestyles
      • Lam V.
      • Teutsch S.
      • Fielding J.
      Hip and knee replacements: a neglected potential savings opportunity.
      and increasing life expectancy of the general population, the prevalence of hip and knee replacements will continue to increase. Hip and knee replacements can improve function and quality of life of individuals with severe arthritis.
      • Maradit Kremers H.
      • Larson D.R.
      • Crowson C.S.
      • et al.
      Prevalence of total hip and knee replacement in the United States.
      ,
      • van der Wees P.J.
      • Wammes J.J.
      • Akkermans R.P.
      • et al.
      Patient-reported health outcomes after total hip and knee surgery in a Dutch University Hospital Setting: results of twenty years clinical registry.
      A major disadvantage, however, is that approximately 6% of all hip and knee replacements need to be revised after 5 years, which rises to as many as 12% after 10 years.
      • Labek G.
      • Thaler M.
      • Janda W.
      • et al.
      Revision rates after total joint replacement: cumulative results from worldwide joint register datasets.
      More than 25% of revisions are attributed to periprosthetic joint infection (PJI), which is a severe complication and associated with substantial morbidity
      • Kapadia B.H.
      • Berg R.A.
      • Daley J.A.
      • et al.
      Periprosthetic joint infection.
      and high costs.
      • Alp E.
      • Cevahir F.
      • Ersoy S.
      • et al.
      Incidence and economic burden of prosthetic joint infections in a university hospital: a report from a middle-income country.
      ,
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      • Lau E.
      • Watson H.
      • et al.
      Economic burden of periprosthetic joint infection in the United States.
      Other causes for revisions are polyethylene wear and aseptic loosening, fractures, and dislocations. Whereas fractures and dislocations can readily be distinguished by radiography or computed tomography (CT), it may be difficult to differentiate PJI from aseptic loosening. Accurate preoperative diagnosis of PJI is highly desirable, however, because it determines the method of treatment. Aseptic loosening is treated in a 1-stage revision procedure (prosthesis removal and direct implantation of a new prosthesis), whereas a 2-stage revision procedure (prosthesis removal and delayed reimplantation of a new prosthesis)
      • Kapadia B.H.
      • Berg R.A.
      • Daley J.A.
      • et al.
      Periprosthetic joint infection.
      is considered the current gold standard treatment of PJI.
      • Charette R.S.
      • Melnic C.M.
      Two-stage revision arthroplasty for the treatment of prosthetic joint infection.

      Pathogenesis of periprosthetic joint infection

      A majority of PJIs occurring within 1 year of surgery are caused by introduction of bacteria at the time of prosthesis placement, which can occur either through direct contact or aerosolized contamination.
      • Tande A.J.
      • Patel R.
      Prosthetic joint infection.
      Once in contact, bacteria colonize the prosthetic surface.
      • Tande A.J.
      • Patel R.
      Prosthetic joint infection.
      Contiguous spread from an adjacent site is the second mechanism by which PJI can be initiated. This can occur either in the early postoperative period (spread of superficial surgical site infection through incompletely healed superficial and deep fascial planes) or also many years postoperatively (if the normal tissue plane is disrupted again by trauma or surgery).
      • Tande A.J.
      • Patel R.
      Prosthetic joint infection.
      The third mechanism, although less frequent, is hematogeneous spread from a remote infection site.
      • Tande A.J.
      • Patel R.
      Prosthetic joint infection.
      Biofilms are complex communities of bacteria embedded in a protective extracellular matrix that forms on prosthetic surfaces.
      • Tande A.J.
      • Patel R.
      Prosthetic joint infection.
      ,
      • Gbejuade H.O.
      • Lovering A.M.
      • Webb J.C.
      The role of microbial biofilms in prosthetic joint infections.
      Their formation is intrinsic to the pathogenesis of chronic PJI and is beneficial to bacterial survival and antibiotic resistance.
      • Tande A.J.
      • Patel R.
      Prosthetic joint infection.
      • Gbejuade H.O.
      • Lovering A.M.
      • Webb J.C.
      The role of microbial biofilms in prosthetic joint infections.
      • Amanatullah D.
      • Dennis D.
      • Oltra E.G.
      • et al.
      Hip and knee section, diagnosis, definitions: proceedings of International Consensus on Orthopedic Infections.

      Definition of periprosthetic joint infection

      In 2018, an updated evidence-based and validated definition for PJI was published.
      • Parvizi J.
      • Tan T.L.
      • Goswami K.
      • et al.
      The 2018 definition of periprosthetic hip and knee infection: an evidence-based and validated criteria.
      This definition is based on major and minor criteria
      • Parvizi J.
      • Tan T.L.
      • Goswami K.
      • et al.
      The 2018 definition of periprosthetic hip and knee infection: an evidence-based and validated criteria.
      (Table 1). Major criteria include 2 positive cultures or the presence of a sinus tract.
      • Parvizi J.
      • Tan T.L.
      • Goswami K.
      • et al.
      The 2018 definition of periprosthetic hip and knee infection: an evidence-based and validated criteria.
      Minor criteria include results from preoperative serum and synovial fluid analysis.
      • Parvizi J.
      • Tan T.L.
      • Goswami K.
      • et al.
      The 2018 definition of periprosthetic hip and knee infection: an evidence-based and validated criteria.
      For patients with inconclusive minor criteria, operative criteria can be used to fulfill the definition of PJI.
      • Parvizi J.
      • Tan T.L.
      • Goswami K.
      • et al.
      The 2018 definition of periprosthetic hip and knee infection: an evidence-based and validated criteria.
      Table 1Proposed scoring-based definition for periprosthetic joint infection
      Adapted from Parvizi J, Tan TL, Goswami K, et al. The 2018 Definition of Periprosthetic Hip and Knee Infection: An Evidence-Based and Validated Criteria. J Arthroplasty. 2018 May;33(5):1309-1314.e2. https://doi.org/10.1016/j.arth.2018.02.078. Epub 2018 Feb 26; with permission.
      Major Criteria (at Least One)Decision
      Two positive cultures of the same organismInfected
      Sinus tract with evidence of communication to the joint or visualization of the prosthesis
      Minor Criteria, PreoperativeScoreDecision
      SerumElevated CRP or D-dimer2≥6 infected

      2–5 possibly infected

      0–1 not infected
      Elevated ESR1
      SynovialElevated white blood cell count or leukocyte esterase3
      Positive α-defensin3
      Elevated polymorphonuclear2
      Elevated CRP1
      Operative Criteria
      For patients with inconclusive minor criteria.
      ScoreDecision
      Preoperative score≥6 infected

      4–5 inconclusive

      ≤3 not infected
      Positive histology3
      Positive purulence3
      Single positive culture2
      a For patients with inconclusive minor criteria.

      Diagnosis of periprosthetic joint infection

      The typical clinical presentation of PJI is a patient with a painful, warm, stiff, and swollen joint. Clinical presentation, however, frequently is atypical, especially in chronic and low-grade infections, and there are no clinical signs that achieve both high sensitivity and high specificity in diagnosing PJI. A painful joint is the most sensitive but least specific clinical finding in PJI.
      • Amanatullah D.
      • Dennis D.
      • Oltra E.G.
      • et al.
      Hip and knee section, diagnosis, definitions: proceedings of International Consensus on Orthopedic Infections.
      Signs of deep tissue involvement (ie, sinus tract, purulence, abscess, and extensive necrosis) are the most specific signs and, when present, justify the condition of major criteria for the diagnosis of PJI.
      • Amanatullah D.
      • Dennis D.
      • Oltra E.G.
      • et al.
      Hip and knee section, diagnosis, definitions: proceedings of International Consensus on Orthopedic Infections.
      ,
      • Parvizi J.
      • Tan T.L.
      • Goswami K.
      • et al.
      The 2018 definition of periprosthetic hip and knee infection: an evidence-based and validated criteria.
      Clinical findings differ based on the type of joint involved (hip or knee) as well as on the timing and presentation of PJI (ie, early postoperative, acute hematogenous, and chronic).
      • Amanatullah D.
      • Dennis D.
      • Oltra E.G.
      • et al.
      Hip and knee section, diagnosis, definitions: proceedings of International Consensus on Orthopedic Infections.
      Preoperative synovial fluid culture and serum and synovial fluid analysis for infection markers may be helpful to rule in or rule out PJI (see Table 1). An important limitation, however, is the considerable percentage of dry taps, that is, cases in which no fluid can be aspirated despite appropriate anatomic location within the prosthetic hip or knee joint capsule. This percentage has been reported to be as high as 23% and it does not imply that PJI is not present.
      • Ali F.
      • Wilkinson J.M.
      • Cooper J.R.
      • et al.
      Accuracy of joint aspiration for the preoperative diagnosis of infection in total hip arthroplasty.
      Other limitations of synovial fluid culture are false-negative results when bacteria are embedded in a biofilm
      • Gbejuade H.O.
      • Lovering A.M.
      • Webb J.C.
      The role of microbial biofilms in prosthetic joint infections.
      and false-positive cultures when synovial fluid samples are contaminated. Even when using the updated evidence-based and validated major and minor criteria for PJI,
      • Parvizi J.
      • Tan T.L.
      • Goswami K.
      • et al.
      The 2018 definition of periprosthetic hip and knee infection: an evidence-based and validated criteria.
      there are patients in whom a diagnosis of PJI cannot be established with certainty preoperatively.
      • Parvizi J.
      • Tan T.L.
      • Goswami K.
      • et al.
      The 2018 definition of periprosthetic hip and knee infection: an evidence-based and validated criteria.
      Moreover, there are conditions (adverse local tissue reaction, crystalline deposition arthropathy, inflammatory arthropathy flare, and infection with slowly growing organisms [such as Propionibacterium acnes and coagulase-negative Staphylococci]) in which the criteria may be inaccurate.
      • Parvizi J.
      • Tan T.L.
      • Goswami K.
      • et al.
      The 2018 definition of periprosthetic hip and knee infection: an evidence-based and validated criteria.

      Role of imaging, including fludeoxyglucose F 18 positron emission tomography

      The diagnostic approach in patients with suspected PJI is variable from center to center.
      • Signore A.
      • Sconfienza L.M.
      • Borens O.
      • et al.
      Consensus document for the diagnosis of prosthetic joint infections: a joint paper by the EANM, EBJIS, and ESR (with ESCMID endorsement).
      It depends on local experience and availability of technological equipment.
      • Signore A.
      • Sconfienza L.M.
      • Borens O.
      • et al.
      Consensus document for the diagnosis of prosthetic joint infections: a joint paper by the EANM, EBJIS, and ESR (with ESCMID endorsement).
      Also, there currently are no published evidence-based guidelines to guide the diagnostic work-up of PJI.
      • Signore A.
      • Sconfienza L.M.
      • Borens O.
      • et al.
      Consensus document for the diagnosis of prosthetic joint infections: a joint paper by the EANM, EBJIS, and ESR (with ESCMID endorsement).
      Table 2 provides a global, descriptive overview of the accuracy of different imaging modalities.
      Table 2Global, descriptive overview of the accuracy of different imaging modalities that may be used to diagnose periprosthetic joint infection
      Imaging ModalitySensitivitySpecificity
      RadiographyLowLow
      CTUnclear
      Insufficient data.
      Unclear
      Insufficient data.
      MRIUnclear
      Insufficient data.
      Unclear
      Insufficient data.
      Bone scintigraphyHighLow
      Labeled leukocyte imagingFairly highFairly high
      18F-FDG PETFairly highFairly high
      Note that accuracy may depend, among others, on diagnostic criteria used and joint site.
      a Insufficient data.
      Radiography usually is the initial imaging modality to evaluate possible PJI.
      • Kapadia B.H.
      • Berg R.A.
      • Daley J.A.
      • et al.
      Periprosthetic joint infection.
      ,
      • Li C.
      • Renz N.
      • Trampuz A.
      Management of periprosthetic joint infection.
      Its sensitivity and specificity are low: osteolysis and periosteal reaction are late findings and also may occur in aseptic loosening.
      • Kapadia B.H.
      • Berg R.A.
      • Daley J.A.
      • et al.
      Periprosthetic joint infection.
      ,
      • Li C.
      • Renz N.
      • Trampuz A.
      Management of periprosthetic joint infection.
      CT
      • Cyteval C.
      • Hamm V.
      • Sarrabère M.P.
      • et al.
      Painful infection at the site of hip prosthesis: CT imaging.
      and magnetic resonance imaging (MRI) using metal artifact reduction sequences may be more accurate, because they can detect soft tissue abnormalities associated with PJI, included among which are periarticular fluid collections, joint effusion, synovitis, lymphadenopathy, and sinus tracts.
      • Fritz J.
      • Lurie B.
      • Miller T.T.
      • et al.
      MR imaging of hip arthroplasty implants.
      • Fritz J.
      • Lurie B.
      • Potter H.G.
      MR imaging of knee arthroplasty implants.
      • Koff M.F.
      • Burge A.J.
      • Koch K.M.
      • et al.
      Imaging near orthopedic hardware.
      The accuracy of these cross-sectional imaging modalities, however, has not yet been widely validated. Granulomatous reactions to wear, the concurrence of adverse local tissue reaction and PJI, and underlying rheumatoid diseases may impede assessment by CT and MRI.
      • Fritz J.
      • Lurie B.
      • Miller T.T.
      • et al.
      MR imaging of hip arthroplasty implants.
      There are several nuclear imaging techniques that can be used to evaluate suspected PJI. Bone scintigraphy with technetium Tc 99m (99mTc)-labeled diphosphonates or, alternatively, sodium fluoride F 18 PET
      • Grant F.D.
      • Fahey F.H.
      • Packard A.B.
      • et al.
      Skeletal PET with 18F-fluoride: applying new technology to an old tracer.
      can be used to assess osteoblastic activity around the prosthesis. Because sensitivity is high,
      • Verberne S.J.
      • Sonnega R.J.
      • Temmerman O.P.
      • et al.
      What is the accuracy of nuclear imaging in the assessment of periprosthetic knee infection? A meta-analysis.
      ,
      • Verberne S.J.
      • Raijmakers P.G.
      • Temmerman O.P.
      The accuracy of imaging techniques in the assessment of periprosthetic hip infection: a systematic review and meta-analysis.
      normal findings can be considered strong evidence against the presence of PJI.
      • Glaudemans A.W.
      • Galli F.
      • Pacilio M.
      • et al.
      Leukocyte and bacteria imaging in prosthetic joint infection.
      Specificity, however, generally is low
      • Verberne S.J.
      • Sonnega R.J.
      • Temmerman O.P.
      • et al.
      What is the accuracy of nuclear imaging in the assessment of periprosthetic knee infection? A meta-analysis.
      ,
      • Verberne S.J.
      • Raijmakers P.G.
      • Temmerman O.P.
      The accuracy of imaging techniques in the assessment of periprosthetic hip infection: a systematic review and meta-analysis.
      ; positive findings can indicate either PJI or aseptic loosening. Moreover, a bone scan may be positive for at least 2 years after hip replacement and at least 5 years after knee replacement due to physiologic bone remodeling.
      • Glaudemans A.W.
      • Galli F.
      • Pacilio M.
      • et al.
      Leukocyte and bacteria imaging in prosthetic joint infection.
      Because bone scintigraphy with 99mTc-labeled diphosphonates is relatively cheap, it may be used as an initial screening test for suspected PJI. Labeled leukocyte imaging has shown superior accuracy for diagnosing PJI compared with bone scintigraphy.
      • Verberne S.J.
      • Sonnega R.J.
      • Temmerman O.P.
      • et al.
      What is the accuracy of nuclear imaging in the assessment of periprosthetic knee infection? A meta-analysis.
      ,
      • Verberne S.J.
      • Raijmakers P.G.
      • Temmerman O.P.
      The accuracy of imaging techniques in the assessment of periprosthetic hip infection: a systematic review and meta-analysis.
      A caveat, however, is the normal physiologic accumulation of white blood cells in the bone marrow, which may be variable from 1 person to another.
      • Glaudemans A.W.
      • Galli F.
      • Pacilio M.
      • et al.
      Leukocyte and bacteria imaging in prosthetic joint infection.
      Furthermore, hematopoietically active marrow usually develops around joint prostheses, producing an alteration of the normal bone marrow distribution. This problem may be overcome by late imaging (after 20–24 hours). In PJI, further accumulation of labeled leukocytes is seen in the late images due to increased uptake in infected areas and reduction in background activity.
      • Signore A.
      • Jamar F.
      • Israel O.
      • et al.
      Clinical indications, image acquisition and data interpretation for white blood cells and anti-granulocyte monoclonal antibody scintigraphy: an EANM procedural guideline.
      Labeled leukocyte scintigraphy has other important drawbacks, including its complexity, high costs, potential hazards due to the direct handling of blood products, and considerable radiation burden.
      • Kwee T.C.
      • Basu S.
      • Alavi A.
      The ongoing misperception that labeled leukocyte imaging is superior to 18F-FDG PET for diagnosing prosthetic joint infection.
      Fludeoxyglucose F 18 (18F-FDG) PET is practically superior, because it is routinely available, provides a completed examination within 1 hour after 18F-FDG administration (rather than 24 hours for labeled leukocyte imaging), and has a favorable safety profile (lack of pathogens in the final product).
      • Kwee T.C.
      • Basu S.
      • Alavi A.
      The ongoing misperception that labeled leukocyte imaging is superior to 18F-FDG PET for diagnosing prosthetic joint infection.

      Principle of fludeoxyglucose F 18 positron emission tomography in infection

      Activated leukocytes use glucose as an energy source and show increased expression of glucose transporters.
      • Glaudemans A.W.
      • Galli F.
      • Pacilio M.
      • et al.
      Leukocyte and bacteria imaging in prosthetic joint infection.
      ,
      • Love C.
      • Tomas M.B.
      • Tronco G.G.
      • et al.
      FDG PET of infection and inflammation.
      In inflammatory conditions, the affinity of glucose transporters for 18F-FDG is increased by various cytokines and growth factors. 18F-FDG is transported into cells by glucose transporters and is phosphorylated by hexokinase enzyme to 18F-FDG-6 phosphate but is not metabolized. The degree of 18F-FDG uptake is related to the metabolic rate and the number of glucose transporters in leukocytes.
      • Love C.
      • Tomas M.B.
      • Tronco G.G.
      • et al.
      FDG PET of infection and inflammation.
      The uptake of 18F-FDG reflects in vivo labeling of the existing and activated cells at the site of PJI soon after 18F-FDG injection.
      • Basu S.
      • Kwee T.C.
      • Saboury B.
      • et al.
      FDG PET for diagnosing infection in hip and knee prostheses: prospective study in 221 prostheses and subgroup comparison with combined (111)In-labeled leukocyte/(99m)Tc-sulfur colloid bone marrow imaging in 88 prostheses.
      In contrast to labeled leukocyte imaging, 18F-FDG uptake does not rely on leukocyte migration. Therefore, treatment with antibiotics is less likely to affect its sensitivity in delineating the PJI site.
      • Basu S.
      • Kwee T.C.
      • Saboury B.
      • et al.
      FDG PET for diagnosing infection in hip and knee prostheses: prospective study in 221 prostheses and subgroup comparison with combined (111)In-labeled leukocyte/(99m)Tc-sulfur colloid bone marrow imaging in 88 prostheses.

      Fludeoxyglucose F 18 positron emission tomography protocol

      Recommendations with regard to patient preparation and precautions, 18F-FDG dose, and image acquisition have been outlined in detail in the European Association of Nuclear Medicine/Society of Nuclear Medicine and Molecular Imaging guideline for 18F-FDG use in inflammation and infection.
      • Jamar F.
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      • Chiti A.
      • et al.
      EANM/SNMMI guideline for 18F-FDG use in inflammation and infection.
      Simultaneous PET and CT (integrated PET/CT) allows for precise allocation of 18F-FDG uptake.
      • von Schulthess G.K.
      • Steinert H.C.
      • Hany T.F.
      Integrated PET/CT: current applications and future directions.
      CT-based PET attenuation correction is susceptible to errors where artifacts occur, particularly in the vicinity of metal implants.
      • van der Vos C.S.
      • Arens A.I.J.
      • Hamill J.J.
      • et al.
      Metal artifact reduction of CT scans to improve PET/CT.
      ,
      • Schabel C.
      • Gatidis S.
      • Bongers M.
      • et al.
      Improving CT-based PET attenuation correction in the vicinity of metal implants by an iterative metal artifact reduction algorithm of CT data and its comparison to dual-energy-based strategies: a phantom study.
      This can result in underestimation and overestimation of 18F-FDG uptake.
      • van der Vos C.S.
      • Arens A.I.J.
      • Hamill J.J.
      • et al.
      Metal artifact reduction of CT scans to improve PET/CT.
      ,
      • Schabel C.
      • Gatidis S.
      • Bongers M.
      • et al.
      Improving CT-based PET attenuation correction in the vicinity of metal implants by an iterative metal artifact reduction algorithm of CT data and its comparison to dual-energy-based strategies: a phantom study.
      There has been recent interest in the use of iterative metal artifact reduction of CT data, which improves PET image quality around prostheses.
      • van der Vos C.S.
      • Arens A.I.J.
      • Hamill J.J.
      • et al.
      Metal artifact reduction of CT scans to improve PET/CT.
      ,
      • Schabel C.
      • Gatidis S.
      • Bongers M.
      • et al.
      Improving CT-based PET attenuation correction in the vicinity of metal implants by an iterative metal artifact reduction algorithm of CT data and its comparison to dual-energy-based strategies: a phantom study.

      Diagnostic performance of fludeoxyglucose F 18 positron emission tomography

      The diagnostic performance of 18F-FDG PET in detecting PJI in hip and knee replacements seems sufficiently high for routine clinical application and has not proved inferior to labeled leukocyte scintigraphy.
      • Verberne S.J.
      • Sonnega R.J.
      • Temmerman O.P.
      • et al.
      What is the accuracy of nuclear imaging in the assessment of periprosthetic knee infection? A meta-analysis.
      ,
      • Verberne S.J.
      • Raijmakers P.G.
      • Temmerman O.P.
      The accuracy of imaging techniques in the assessment of periprosthetic hip infection: a systematic review and meta-analysis.
      ,
      • Kwee T.C.
      • Basu S.
      • Alavi A.
      The ongoing misperception that labeled leukocyte imaging is superior to 18F-FDG PET for diagnosing prosthetic joint infection.
      ,
      • Basu S.
      • Kwee T.C.
      • Saboury B.
      • et al.
      FDG PET for diagnosing infection in hip and knee prostheses: prospective study in 221 prostheses and subgroup comparison with combined (111)In-labeled leukocyte/(99m)Tc-sulfur colloid bone marrow imaging in 88 prostheses.
      A meta-analysis reported a pooled sensitivity of 86% (95% CI, 80% to 90%) and a pooled specificity of 93% (95% CI, 90% to 95%) for hip prostheses.
      • Verberne S.J.
      • Raijmakers P.G.
      • Temmerman O.P.
      The accuracy of imaging techniques in the assessment of periprosthetic hip infection: a systematic review and meta-analysis.
      Another meta-analysis reported a pooled sensitivity of 70% (95% CI, 56% to 81%) and a pooled specificity of 84% (95% CI, 76% to 90%) for knee prostheses.
      • Verberne S.J.
      • Sonnega R.J.
      • Temmerman O.P.
      • et al.
      What is the accuracy of nuclear imaging in the assessment of periprosthetic knee infection? A meta-analysis.
      In addition, 18F-FDG PET has shown useful in patients with nonspecific clinical presentation (ie, without apparent clinical signs and symptoms, such as absence of a sinus tract).
      • Zajonz D.
      • Zieme A.
      • Prietzel T.
      • et al.
      Periprosthetic joint infections in modular endoprostheses of the lower extremities: a retrospective observational study in 101 patients.
      ,
      • Kwee R.M.
      • Broos W.A.
      • Brans B.
      • et al.
      Added value of 18F-FDG PET/CT in diagnosing infected hip prosthesis.
      Furthermore, it has additional value to conventional tests (including radiography, erythrocyte sedimentation rate [ESR]/C-reactive protein [CRP] testing, and joint aspiration culture and white blood cell count) in diagnosing PJI (ie, it increases accuracy).
      • Kwee R.M.
      • Broos W.A.
      • Brans B.
      • et al.
      Added value of 18F-FDG PET/CT in diagnosing infected hip prosthesis.

      Fludeoxyglucose F 18 positron emission tomography evaluation

      It is important to be aware that 18F-FDG PET uptake in healing bone is normal within 3 months after surgery.
      • Zhuang H.
      • Sam J.W.
      • Chacko T.K.
      • et al.
      Rapid normalization of osseous FDG uptake following traumatic or surgical fractures.
      Differentiating between PJI and inflammation secondary due to foreign body reaction and/or aseptic loosening can be difficult. In noninfected hip prostheses, 18F-FDG uptake is commonly seen around the neck
      • Gelderman S.J.
      • Jutte P.C.
      • Boellaard R.
      • et al.
      18F-FDG-PET uptake in non-infected total hip prostheses.
      • Zhuang H.
      • Chacko T.K.
      • Hickeson M.
      • et al.
      Persistent non-specific FDG uptake on PET imaging following hip arthroplasty.
      • Vanquickenborne B.
      • Maes A.
      • Nuyts J.
      • et al.
      The value of (18)FDG-PET for the detection of infected hip prosthesis.
      • Aydin A.
      • Yu J.Q.
      • Zhuang H.
      • et al.
      Patterns of 18F-FDG PET images in patients with uncomplicated total hip arthroplasty.
      (Figs. 1 and 2), which may be explained by wear of components and an adverse tissue reaction.
      • Gelderman S.J.
      • Jutte P.C.
      • Boellaard R.
      • et al.
      18F-FDG-PET uptake in non-infected total hip prostheses.
      Furthermore, physiologic 18F-FDG uptake also may be present at the lateral and medial sides of the acetabular cup
      • Gelderman S.J.
      • Jutte P.C.
      • Boellaard R.
      • et al.
      18F-FDG-PET uptake in non-infected total hip prostheses.
      (see Fig. 2), at the proximal portion of the femoral component,
      • Aydin A.
      • Yu J.Q.
      • Zhuang H.
      • et al.
      Patterns of 18F-FDG PET images in patients with uncomplicated total hip arthroplasty.
      and at the distal tip of the femoral component.
      • Zhuang H.
      • Chacko T.K.
      • Hickeson M.
      • et al.
      Persistent non-specific FDG uptake on PET imaging following hip arthroplasty.
      The level of physiologic 18F-FDG uptake in uncemented hip prostheses is influenced by the age and probably the type of prosthesis.
      • Gelderman S.J.
      • Jutte P.C.
      • Boellaard R.
      • et al.
      18F-FDG-PET uptake in non-infected total hip prostheses.
      In noninfected hip prostheses, there should be no 18F-FDG uptake in the periprosthetic soft tissues, except for the soft tissue near the greater trochanter.
      • Gelderman S.J.
      • Jutte P.C.
      • Boellaard R.
      • et al.
      18F-FDG-PET uptake in non-infected total hip prostheses.
      18F-FDG PET can identify soft tissue abscesses, which are not apparent on clinical examination (Fig. 3) and, when present, it justifies the condition of major criteria for the diagnosis of PJI.
      • Amanatullah D.
      • Dennis D.
      • Oltra E.G.
      • et al.
      Hip and knee section, diagnosis, definitions: proceedings of International Consensus on Orthopedic Infections.
      ,
      • Parvizi J.
      • Tan T.L.
      • Goswami K.
      • et al.
      The 2018 definition of periprosthetic hip and knee infection: an evidence-based and validated criteria.
      18F-FDG uptake at the middle portion of the femoral shaft is virtually never seen in asymptomatic patients or in those with aseptic loosening and is highly suspicious for PJI (Fig. 4).
      • Gelderman S.J.
      • Jutte P.C.
      • Boellaard R.
      • et al.
      18F-FDG-PET uptake in non-infected total hip prostheses.
      ,
      • Zhuang H.
      • Chacko T.K.
      • Hickeson M.
      • et al.
      Persistent non-specific FDG uptake on PET imaging following hip arthroplasty.
      ,
      • Aydin A.
      • Yu J.Q.
      • Zhuang H.
      • et al.
      Patterns of 18F-FDG PET images in patients with uncomplicated total hip arthroplasty.
      ,
      • Verberne S.J.
      • Temmerman O.P.P.
      • Vuong B.H.
      • et al.
      Fluorodeoxyglucose positron emission tomography imaging for diagnosing periprosthetic hip infection: the importance of diagnostic criteria.
      Most studies that have been performed to date have evaluated visual 18F-FDG uptake patterns associated with aseptic loosening or PJI. There is no accepted standardized uptake value (SUV) threshold to diagnose PJI. More importantly, the intensity of 18F-FDG uptake is less important than the location of increased 18F-FDG uptake to diagnose PJI.
      • Chacko T.K.
      • Zhuang H.
      • Stevenson K.
      • et al.
      The importance of the location of fluorodeoxyglucose uptake in periprosthetic infection in painful hip prostheses.
      Hip prostheses, which show aseptic loosening, can be accompanied by an intense inflammatory response involving large numbers of leukocytes
      • Palestro C.J.
      Radionuclide imaging of musculoskeletal infection: a review.
      and, as a result, demonstrate intense 18F-FDG uptake, with SUVs as high as 7.
      • Chacko T.K.
      • Zhuang H.
      • Stevenson K.
      • et al.
      The importance of the location of fluorodeoxyglucose uptake in periprosthetic infection in painful hip prostheses.
      Therefore, using increased 18F-FDG uptake as the sole criterion to diagnose PJI in hip prostheses results in false-positive results.
      • Chacko T.K.
      • Zhuang H.
      • Stevenson K.
      • et al.
      The importance of the location of fluorodeoxyglucose uptake in periprosthetic infection in painful hip prostheses.
      The pattern of 18F-FDG uptake around noninfected knee prostheses has been less well documented than that of hip prostheses. Nonspecific synovial 18F-FDG uptake in knee prostheses has been reported by several studies
      • Love C.
      • Marwin S.E.
      • Tomas M.B.
      • et al.
      Diagnosing infection in the failed joint replacement: a comparison of coincidence detection 18F-FDG and 111In-labeled leukocyte/99mTc-sulfur colloid marrow imaging.
      • Delank K.S.
      • Schmidt M.
      • Michael J.W.
      • et al.
      The implications of 18F-FDG PET for the diagnosis of endoprosthetic loosening and infection in hip and knee arthroplasty: results from a prospective, blinded study.
      • Van Acker F.
      • Nuyts J.
      • Maes A.
      • et al.
      FDG-PET, 99mtc-HMPAO white blood cell SPET and bone scintigraphy in the evaluation of painful total knee arthroplasties.
      • Mayer-Wagner S.
      • Mayer W.
      • Maegerlein S.
      • et al.
      Use of 18F-FDG-PET in the diagnosis of endoprosthetic loosening of knee and hip implants.
      (Fig. 5). On the other hand, 18F-FDG uptake at the bone-prosthesis interface of the femoral or tibial component has been consistently reported as diagnostic criterion for PJI in knee prostheses
      • Verberne S.J.
      • Sonnega R.J.
      • Temmerman O.P.
      • et al.
      What is the accuracy of nuclear imaging in the assessment of periprosthetic knee infection? A meta-analysis.
      (Fig. 6). The influence of 18F-FDG uptake, however, at specific bone-prosthesis locations on diagnostic performance has not been reported yet, to the authors’ knowledge. Table 3 summarizes areas of nonspecific 18F-FDG uptake and criteria for PJI in hip and knee prostheses, based on available evidence.
      Figure thumbnail gr1
      Fig. 1Nonspecific 18F-FDG uptake in a 66-year-old woman with bilateral asymptomatic total hip prostheses. This patient underwent 18F-FDG PET to evaluate a lung lesion. Coronal PET image (B) shows nonspecific 18F-FDG uptake around the neck of the left hip prosthesis (arrowheads), with corresponding CT image (A).
      Figure thumbnail gr2
      Fig. 2Nonspecific 18F-FDG uptake in a 70-year-old man with asymptomatic right total hip prosthesis. This patient underwent 18F-FDG PET to identify the cause of fever of unknown origin. Coronal PET image (B) shows nonspecific 18F-FDG uptake around the neck (arrowheads) and nonspecific 18F-FDG uptake at lateral side of the acetabular cup (arrow), with corresponding CT image (A).
      Figure thumbnail gr3
      Fig. 3PJI in an 80-year-old woman with painful left hip prosthesis. Axial (A, B) and coronal (C, D) CT and PET images are displayed. There is a fluid collection in the left iliacus (arrows [A, C]) muscle, which shows peripheral 18F-FDG uptake and no central 18F-FDG uptake (arrows [B, D]), compatible with an abscess. This abscess was not suspected clinically and extended caudally to the left hip joint. In addition, there is 18F-FDG uptake at the bone-prosthesis interface around the acetabular cup and at the proximal femoral stem (arrowheads [D]).
      Figure thumbnail gr4
      Fig. 4PJI in a patient with bilateral prosthesis. Coronal PET image reveals 18F-FDG uptake at the middle portion of the femoral shaft at the bone-prosthesis interface (arrow), which is highly suspicious for PJI. PJI was confirmed by further assessment.
      (From Saboury B, Ziai P, Parsons M, et al. Promising Roles of PET in Management of Arthroplasty-Associated Infection. PET Clin 2012; 7:139-50; with permission.)
      Figure thumbnail gr5
      Fig. 5Nonspecific synovial 18F-FDG uptake in an asymptomatic knee prosthesis of a 70-year-old man, as shown on coronal (A) and sagittal (B) PET images (arrowheads), with corresponding CT images (C, D).
      Figure thumbnail gr6
      Fig. 6PJI in a patient with a left knee prosthesis. Coronal PET image demonstrates a focus of intense 18F-FDG uptake in the medial aspect of femoral component at the bone-prosthesis interface (arrow). Operative findings and histopathology confirmed the presence of infection.
      (From Saboury B, Ziai P, Parsons M, et al. Promising Roles of PET in Management of Arthroplasty-Associated Infection. PET Clin 2012; 7:139-50; with permission.)
      Table 3Areas of nonspecific fludeoxyglucose F 18 uptake and criteria for periprosthetic joint infection in hip and knee prostheses, based on available evidence
      Areas of Nonspecific Fludeoxyglucose F 18 UptakeCriteria for Periprosthetic Joint Infection
      Hip
      • Around the neck of the prosthesis
      • Lateral and medial sides of the acetabular cup
      • Proximal portion of the femoral component
      • Distal portion of the femoral component
      • 18F-FDG uptake at the middle portion of the femoral component
      Knee
      • Synovium
      • 18F-FDG uptake at the bone-prosthesis interface

      Role of fludeoxyglucose F 18 positron emission tomography in other prosthetic joints than hip and knee

      The number of shoulder replacements is growing faster than ever.
      • Kim S.H.
      • Wise B.L.
      • Zhang Y.
      • et al.
      Increasing incidence of shoulder arthroplasty in the United States.
      The occurrence rate of PJI after total shoulder replacement is approximately 1% to 3.9% and can be even higher in reversed designs due to an increase in dead space and hematoma formation.
      • Pinder E.M.
      • Ong J.C.
      • Bale R.S.
      • et al.
      Ten questions on prosthetic shoulder infection.
      Of all revision shoulder operations, 12% are due to PJI.
      • Pinder E.M.
      • Ong J.C.
      • Bale R.S.
      • et al.
      Ten questions on prosthetic shoulder infection.
      Because the number of patients who undergo shoulder arthroplasty is growing fast,
      • Kim S.H.
      • Wise B.L.
      • Zhang Y.
      • et al.
      Increasing incidence of shoulder arthroplasty in the United States.
      ,
      • Pinder E.M.
      • Ong J.C.
      • Bale R.S.
      • et al.
      Ten questions on prosthetic shoulder infection.
      it can be anticipated that the number of patients with PJI also will increase. The value of 18F-FDG PET in evaluating shoulder PJI, however, has not yet been extensively investigated. The results of a recent study suggested that 18F-FDG PET has poor diagnostic accuracy in diagnosing low-grade PJI of the shoulder.
      • Falstie-Jensen T.
      • Daugaard H.
      • Søballe K.
      • et al.
      ROSA Study Group
      Labeled white blood cell/bone marrow single-photon emission computed tomography with computed tomography fails in diagnosing chronic periprosthetic shoulder joint infection.
      In addition, the performance and place of 18F-FDG PET in the diagnostic decision tree of suspected PJI in other less common arthroplasty sites, such as the elbow and ankle, also remains to be investigated. The potential of 18F-FDG PET in evaluating elbow prosthesis already has been demonstrated,
      • Balasubramanian Harisankar Natrajan C.
      • Mittal B.R.
      • Bhattacharya A.
      • et al.
      Interesting image. Aseptic loosening of elbow prostheses diagnosed on F-18 FDG PET/CT.
      but diagnostic accuracy data are not available yet.

      Future perspectives

      Although diagnostic performance of 18F-FDG PET in detecting hip and knee PJI seems sufficiently high for clinical use, results from several individual studies were heterogeneous.
      • Verberne S.J.
      • Sonnega R.J.
      • Temmerman O.P.
      • et al.
      What is the accuracy of nuclear imaging in the assessment of periprosthetic knee infection? A meta-analysis.
      ,
      • Verberne S.J.
      • Raijmakers P.G.
      • Temmerman O.P.
      The accuracy of imaging techniques in the assessment of periprosthetic hip infection: a systematic review and meta-analysis.
      Importantly, the definition of PJI has evolved over the years with the most recent updated evidence-based and validated definition for PJI published in 2018.
      • Parvizi J.
      • Tan T.L.
      • Goswami K.
      • et al.
      The 2018 definition of periprosthetic hip and knee infection: an evidence-based and validated criteria.
      Most 18F-FDG PET studies performed so far, however, used various other/older definitions of PJI, which may have been an important source of heterogeneity. Standardization of 18F-FDG PET acquisition protocols, diagnostic criteria, and reference standard is required to further explore potential causes of heterogeneity (including type and age of prosthesis) and to further validate this method, preferably by multicenter studies. Large prospective studies comparing the diagnostic performance of 18F-FDG PET and labeled leukocyte imaging for PJI are anticipated.
      • Signore A.
      • Sconfienza L.M.
      • Borens O.
      • et al.
      Consensus document for the diagnosis of prosthetic joint infections: a joint paper by the EANM, EBJIS, and ESR (with ESCMID endorsement).
      Simultaneous PET and MRI (integrated PET/MRI) has high potential to improve the noninvasive diagnosis of PJI in 1 single examination, because it combines the functional information gathered from PET and the excellent anatomic detail and soft tissue contrast from MRI.
      • Ehman E.C.
      • Johnson G.B.
      • Villanueva-Meyer J.E.
      • et al.
      PET/MRI: where might it replace PET/CT?.

      Summary

      Diagnosing PJI can be a challenge, especially for chronic and low-grade infections. The diagnostic performance of 18F-FDG PET in detecting PJI in hip and knee replacements seems sufficiently high for routine clinical application and adds to conventional tests. Location rather than intensity of 18F-FDG uptake is critical in diagnosing hip and knee PJI. 18F-FDG uptake at the middle portion of the femoral component and 18F-FDG uptake at the bone-prosthesis interface can be considered positive criteria for PJI in hip and knee prostheses, respectively. The role of 18F-FDG PET in other prosthetic joints remains to be investigated.

      Disclosure

      All authors have no disclosures to declare.

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