FDG-PET takes lead role in suspected or proven infection

In recent years, several groups have demonstrated the promise of FDG-PET imaging in the management of patients with suspected and/or documented infection. This technique appears to be particularly useful in the evaluation of osteomyelitis, infected prostheses, fever of unknown origin, and acquired immunodeficiency syndrome. Considering the extraordinary sensitivity of FDG-PET in detecting disease activity and nonactivity in malignant and benign disorders, this powerful method may prove valuable also in a variety of infectious processes. We speculate that it will be widely employed in the near future for detecting, characterizing, and monitoring patients with suspected or proven infection.

FDG-PET offers several advantages over existing imaging techniques (both structural and functional) in the diagnosis of infectious diseases. Radiolabeled white blood cell (WBC) imaging, which has been used for three decades, suffers from substantial shortcomings. It is time consuming, labor intensive, costly, and requires more than 24 hours to be completed. Moreover, conventional planar images, which result from this modality, limit precise localization of affected sites and have low sensitivity compared with tomographic techniques. Bone marrow imaging, essential for proper interpretation of WBC scans, further complicates the process and increases the cost. In addition, the risk of contamination with a variety of pathogens is a serious concern with WBC imaging.1

FDG-PET has the potential to overcome many shortcomings associated with the WBC technique. These include feasibility of securing diagnostic results within one and a half to two hours, excellent spatial resolution and, therefore, accurate anatomical localization of the sites of abnormality, high target-to-background contrast ratio, and, finally, the ability to detect infection in the axial skeleton, where WBC scanning is of limited value. Availability of PET/CT as a practical tool has further enhanced the role of this method in these settings.

When compared with the anatomical modalities, FDG-PET imaging can be employed as a whole-body imaging technique, providing excellent results in the presence of metallic implants. By assessing the metabolic activity of the inflammatory cells directly at the diseased sites, the technique achieves high specificity.

CHRONIC OSTEOMYELITIS

In general, FDG-PET appears to be highly sensitive for detecting chronic osteomyelitis, and it is of particular diagnostic value in patients who have been treated with antibiotics prior to imaging.2 In the latter setting, the sensitivity of WBC imaging is significantly affected by the prior use of antibiotics. Data in the literature consistently support the superiority of FDG-PET over imaging with radiolabeled WBCs to detect infectious processes with an accuracy exceeding 90%.3-5 Three-phase bone scanning with technetium-99m methylene diphosphonate, which has long been used to evaluate patients with suspected osteomyelitis, has a very poor specificity, particularly in patients with prior trauma to the bone, metal implants, and neuropathic joints.

In patients who have received antibiotic therapy prior to imaging, WBC imaging has a low sensitivity due to poor migration of the labeled leukocytes to the sites of infection.6 In addition, this technique is of limited value in the assessment of osteomyelitis involving the axial skeleton, where its sensitivity is approximately 60% for acute7 and 21% for chronic8 osteomyelitis. In these settings, FDG-PET clearly appears to be the study of choice.

Bone marrow edema or enhancement seen on MRI is nonspecific and the modality may not be able to distinguish between a reactive phenomenon and infection in patients who have undergone prior surgical interventions. In addition, diagnostic accuracy of both CT and MRI to evaluate osteomyelitis generally decreases in the presence of metallic implants due to streak and susceptibility artifacts, respectively.

COMPLICATED DIABETIC FOOT

Diabetic foot infections make up up to 33% of total cases of bone infections and are important to diagnose promptly to prevent surgical amputation of the foot (Figure 1). Preliminary data provide evidence for an important role for FDG-PET imaging in this setting. This technique can differentiate between Charcot neuroarthropathy and osteomyelitis with relatively high precision.9 FDG-PET/CT has been shown to be highly accurate in detecting osteomyelitis in patients with complicated diabetic foot.10 In contrast to malignant lesions, the effects of hyperglycemia on the accuracy of FDG-PET in detecting pedal osteomyelitis in diabetic patients appear to be minimal, and the quality of the images generated is optimal when serum glucose levels are less than 250 mg/dL.11 We believe that with the evolution of PET/CT fusion imaging in clinical practice, this approach will be the study of choice for evaluating the complicated diabetic foot, especially in the setting of neuropathic osteoarthropathy (Figure 2).

PAINFUL ARTHROPLASTY

Differentiating mechanical aseptic loosening of a prosthesis from an infected implant in painful arthroplasties poses a significant challenge to attending physicians. Treatment of aseptic loosening usually requires one-step revision surgery, whereas infection is a serious complication and should be treated adequately before proceeding with insertion of a prosthesis. Between 1990 and 2002, the rate of primary total hip arthroplasties per 100,000 persons increased by approximately 50% in the U.S., and the corresponding rate of primary total knee arthroplasties almost tripled. The rate of revision total hip arthroplasties increased by 3.7 procedures per 100,000 persons per decade, and that of revision total knee arthroplasties by 5.4 procedures per 100,000 persons per decade.12

However, only 2% to 4% of patients with a painful prosthesis (less than 1% of total population undergoing total hip arthroplasty) are found to have periprosthetic infection following the initial surgery, which increases to 20% to 30% following revision surgeries.13 Therefore, the implications for an accurate noninvasive diagnosis are substantial in these patients.

FDG-PET shows great potential for detecting infection in hip prostheses, and, to a lesser extent, in knee prostheses. This technique has advantages over anatomical imaging modalities in that it is not affected by the metal implants, provides higher resolution images than those of the conventional planar nuclear medicine techniques, and is exquisitely sensitive. Based on the data generated at Penn and other centers, a specific FDG uptake pattern for hip prosthesis infection has been defined: The presence of FDG uptake at the bone-prosthesis interface at the midshaft portion of the prosthesis is very suggestive of infected implant (Figures 3 and 4). By adopting this criterion, the accuracy of FDG-PET exceeds 90%, as noted in several studies reported in the literature.14-16

We must point out that some degree of inflammation is frequently noted around the femoral neck component of the prosthesis, which persists sometimes for years after the initial surgery. It is generally noninfectious in nature.17 Recent data from a relatively large number of patients enrolled in a prospective study at our institution show excellent results.18 Based on the existing literature and our own experience, we believe FDG-PET will likely play an important role in the management of complicated lower limb prostheses, especially when the criteria and the methodology that have been described in well-designed prospective studies are employed.

FEVER OF UNKNOWN ORIGIN

Among all causes of fever of unknown origin (FUO), infections account for the most, followed by malignancy and noninfectious inflammatory diseases. Accurate localization and characterization of the underlying cause of FUO substantially improves the management of these patients. Gallium-67 citrate, which until recent years was the most commonly used radiotracer for the evaluation of FUO,19 has a relatively low diagnostic yield in this population. On the other hand, radiolabeled WBC imaging is suitable only for the detection of a focal occult infection but is of limited value even in this setting.20 The nonspecificity of FDG is of great importance in evaluating patients with FUO because it accumulates in infections, malignancies, and aseptic inflammatory diseases, which are the three major causes of FUO.

Meller et al reported a sensitivity of 81% and specificity of 86% for FDG-PET and a sensitivity and specificity of 67% and 78%, respectively, for Ga-67 SPECT.21 Stumpe et al22 reported 98% sensitivity, 75% specificity, and 91% accuracy for FDG-PET in 39 patients with suspected infections. Blockmans et al23 studied 58 patients with FUO prospectively and established a final diagnosis in 64% of them. Due to varying definitions of FUO and the lack of a structured diagnostic protocol, reports have varied with regard to the efficacy of this modality. However, FDG-PET appears to enhance the role of conventional techniques in 40% to 70% of the patients. Aseptic inflammation by several noninfectious disease processes can also be detected and characterized with FDG-PET with reasonable accuracy.24-34 PET/CT fusion imaging is likely to play a major role in the future in treating patients

with FUO.

EVALUATION OF AIDS PATIENTS

The literature regarding the role of FDG-PET in HIV-infected patients is still evolving. The major initial research has involved the evaluation and characterization of central nervous system lesions. Current data show that PET is especially valuable in differentiating lymphomas from nonmalignant lesions (such as toxoplasmosis) affecting the CNS. Quantitative assessment has shown that the standardized uptake values of toxoplasmosis are significantly lower than those of lymphoma, with virtually no overlap between the uptake values of the two conditions.35-40

Several small series and case vignettes have been reported in the literature with regard to the utility of FDG-PET in various soft-tissue infections. It appears to be valuable in the evaluation of possible infection of vascular grafts.41-43 Fukuchi et al, in a study of 33 consecutive patients with suspected aortic prosthetic graft infection, concluded that employing the characteristic FDG uptake pattern (diffuse and intense) as a diagnostic criterion made the efficacy of FDG-PET superior to that of CT in the assessment of patients with suspected aortic graft infection.43 When focal uptake was set as the positive indicator for infection, the specificity and positive predictive value of FDG-PET with regard to the diagnosis of aortic graft infection improved to 95%. FDG-PET/CT is reported to have an even higher accuracy in detecting vascular graft infection.43,44

We believe FDG-PET would be particularly valuable in difficult clinical settings where the conventional modalities fail to provide an accurate diagnosis. With time, the list of these indications is likely to grow.

Akin to what has been observed with malignant disorders, FDG-PET holds great promise in monitoring response to therapy in benign disorders, including infections and inflammatory processes. Consequently, in recent years, FDG-PET has been proposed as an effective tool in assessing the efficacy of various therapies. The diseases that have been studied so far include invasive aspergillosis,45 hepatic cyst infection,46 lung abscess caused by Candida infection,47 Pneumocystis carinii pneumonia,48 alveolar echinococcosis,49 salmonella vertebral osteomyelitis,50 and chronic osteomyelitis of the mandible.51 In these reports, the critical role for FDG-PET has been demonstrated in monitoring efficacy of therapeutic interventions.

The role of FDG-PET imaging is rapidly evolving in the management of patients with suspected or proven infectious disorders. Initial results are greatly encouraging. Its role in the management of patients with osteomyelitis, infected prostheses, fever of unknown origin, diabetic foot, and AIDS have been extensively investigated and described, and the list is likely to grow rapidly in the coming years. This modality shows several practical advantages over the currently used structural imaging techniques or conventional scintigraphic methods and hence is likely to be employed widely for the management of these diseases.

Acknowledgements

This work was supported in part by Public Health Services Research Grants R01-DK063579-03 and R01-AR048241 from the National Institute of Health (NIH). This work was also supported in part by the International Union against Cancer (UICC), Geneva, Switzerland, under the ACSBI fellowship.

References

• 1. Meller J, Ivancevic V. Conrad M, et al. Clinical value of immunoscintigraphy in patients with fever of unknown origin. J Nucl Med 1998;39(7):1248-1253.

• 2. Zhuang H, Duarte PS, Pourdehand M, et al. Exclusion of chronic osteomyelitis with F-18 fluorodeoxyglucose positron emission tomographic imaging. Clin Nucl Med 2000;25(4):281-284.

• 3. de Winter F, van de Wiele C, Vogelaers D, et al. Fluorine-18 fluorodeoxyglucose-position emission tomography: a highly accurate imaging modality for the diagnosis of chronic musculoskeletal infections. J Bone Joint Surg Am 2001;83-A(5):651-660.

• 4. Guhlmann A, Brecht-Krauss D, Suger G, et al. Fluorine-18-FDG PET and technetium-99m antigranulocyte antibody scintigraphy in chronic osteomyelitis. J Nucl Med 1998;39(12):2145-2152.

• 5. Kalicke T, Schmitz A, Risse JH, et al. Fluorine-18 fluorodeoxyglucose PET in infectious bone diseases: results of histologically confirmed cases. Eur J Nucl Med 2000;27(5):524-528.

• 6. El Esper I, Dacquet V, Paillard J, et al. 99Tcm-HMPAO-labelled leucocyte scintigraphy in suspected chronic osteomyelitis related to an orthopaedic device: clinical usefulness. Nucl Med Commun 1992;13(11):799-805.

• 7. Palestro CJ, Kim CK, Swyer AJ, et al. Radionuclide diagnosis of vertebral osteomyelitis: indium-111-leukocyte and technetium-99m-methylene diphosphonate bone scintigraphy. J Nucl Med 1991;32(10):1861-1865.

• 8. Termaat MF, Raijmakers PG, Scholten HJ, et al. The accuracy of diagnostic imaging for the assessment of chronic osteomyelitis: a systematic review and meta-analysis. J Bone Joint Surg Am 2005;87-A(11):2464-2471.

• 9. Basu S, Chryssikos T, Houseni M, et al. Potential role of FDG PET in the setting of diabetic neuro-osteoarthropathy: can it differentiate uncomplicated Charcot's neuroarthropathy from osteomyelitis and soft-tissue infection? Nucl Med Commun 2007;28(6):465-472.

• 10. Keidar Z, Militianu D, Melamed E, et al. The diabetic foot: initial experience with 18F-FDG PET/CT. J Nucl Med 2005;46(3):444-449.

• 11. Zhuang HM, Cortes-Blanco A, Pourdehnad M, et al. Do high glucose levels have differential effect on FDG uptake in inflammatory and malignant disorders? Nucl Med Commun 2001;22(10):1123-1128.

• 12. Kurtz S, Mowat F, Ong K, et al. Prevalence of primary and revision total hip and knee arthroplasty in the United States from 1990 through 2002. J Bone Joint Surg Am 2005 Jul;87(7):1487-1497.

• 13. Baron JA, Barrett J, Katz JN, Liang MH. Total hip arthroplasty: use and select complications in the US Medicare population. Am J Public Health 1996;86(1):70-72.

• 14. Mumme T, Reinartz P, Alfer J, et al. Diagnostic values of positron emission tomography versus triple-phase bone scan in hip arthroplasty loosening. Arch Orthop Trauma Surg 2005;125(5):322-329.

• 15. Reinartz P, Mumme T, Hermanns B, et al. Radionuclide imaging of the painful hip arthroplasty: positron-emission tomography versus triple-phase bone scanning. J Bone Joint Surg Br 2005;87-B(4):465-470.

• 16. Zhuang H, Duarte PS, Pourdehnad M, et al. The promising role of 18F-FDG PET in detecting infected lower limb prosthesis implants. J Nucl Med 2001;42(1):44-48.

• 17. Zhuang H, Chacko TK, Hickeson M, et al. Persistent non-specific FDG uptake on PET imaging following hip arthroplasty. Eur J Nucl Med Mol Imaging 2002;29(10):1328-1333.

• 18. Pill SG, Parvizi J, Tang PH, et al. Comparison of fluorodeoxyglucose positron emission tomography and (111)indium-white blood cell imaging in the diagnosis of periprosthetic infection of the hip. J Arthroplasty 2006;21(6 Suppl 2):91-97.

• 19. Knockaert DC, Mortelmans LA, De Roo MC, Bobbaers HJ. Clinical value of gallium-67 scintigraphy in evaluation of fever of unknown origin. Clin Infect Dis 1994;18(4):601-605.

• 20. Kaiser S, Jacobsson H, Hirsch G. Specific or superfluous? Doubtful clinical value of granulocyte scintigraphy in osteomyelitis in children. J Pediatr Orthop B 2001;10(2):109-112.

• 21. Meller J, Altenvoerde G, Munzel U, et al. Fever of unknown origin: prospective comparison of [18F]FDG imaging with a double-head coincidence camera and gallium-67 citrate SPET. Eur J Nucl Med 2000;27(11):1617-1625.

• 22. Stumpe KD, Dazzi H, Schaffner A, et al. Infection imaging using whole-body FDG-PET. Eur J Nucl Med 2000;27(7):822-832.

• 23. Blockmans D, Knockaert D, Maes A, et al. Clinical value of [(18)F]fluoro-deoxyglucose positron emission tomography for patients with fever of unknown origin. Clin Infect Dis 2001;32(2):191-196.

• 24. Alavi A, Buchpiguel CA, Loessner A. Is there a role for FDG PET imaging in the management of patients with sarcoidosis? J Nucl Med 1994;35(10):1650-1652.

• 25. Andrews J, Mason JC. Takayasu's arteritis-recent advances in imaging offer promise. Rheumatology (Oxford) 2007;46(1):6-15.

• 26. Bleeker-Rovers CP, Bredie SJ, van der Meer JW, et al. F-18-fluorodeoxyglucose positron emission tomography in diagnosis and follow-up of patients with different types of vasculitis. Neth J Med 2003;61(10):323-329.

• 27. Brodmann M, Lipp RW, Passath A, et al. The role of 2-18F-fluoro-2-deoxy-D-glucose positron emission tomography in the diagnosis of giant cell arteritis of the temporal arteries. Rheumatology (Oxford) 2004;43(2):241-242.

• 28. de Leeuw K, Bijl M, Jager PL. Additional value of positron emission tomography in diagnosis and follow-up of patients with large vessel vasculitides. Clin Exp Rheumatol 2004;22(6 Suppl 36): S21-26.

• 29. Hara M, Goodman PC, Leder RA. FDG-PET finding in early-phase Takayasu arteritis. JCAT 1999;23(1):16-28.

• 30. Lewis PJ, Salama A. Uptake of fluorine-18-fluorodeoxyglucose in sarcoidosis. J Nucl Med 1994;35(10):1647-1649.

• 31. Li YJ, Zhang Y, Gao S, Bai RJ. Cervical and axillary lymph node sarcoidosis misdiagnosed as lymphoma on F-18 FDG PET-CT. Clin Nucl 2007;32(3):262-264.

• 30. Meller J, Strutz F, Siefker U, et al. Early diagnosis and follow-up of aortitis with [(18)F]FDG PET and MRI. Eur J Nucl Med Mol Imaging 2003;30(5):730-736.

• 33. Zhuang H, Alavi A. 18-fluorodeoxyglucose positron emission tomographic imaging in the detection and monitoring of infection and inflammation. Semin Nucl Med 2002;32(1):47-59.

• 34. Zhuang H, Yu JQ, Alavi A. Applications of fluorodeoxyglucose-PET imaging in the detection of infection and inflammation and other benign disorders. Radiol Clin North Am 2005;43(1):121-134.

• 35. O'Doherty MJ, Barrington SF, Campbell M, et al. PET scanning and the human immunodeficiency virus-positive patient. J Nucl Med 1997;38(10):1575-1583.

• 36. Scharko AM, Perlman SB, Hinds PW, et al. Whole body positron emission tomography imaging of simian immunodeficiency virus-infected rhesus macaques. Proc Natl Acad Sci USA 1996;93(13):6425-6430.

• 37. Scharko AM, Perlman SB, Pyzalski RW, et al. Whole-body positron emission tomography in patients with HIV-1 infection. Lancet 2003;362(9388):959-961.

• 38. Hoffman JM, Waskin HA, Schifter T, et al. FDG-PET in differentiating lymphoma from nonmalignant central nervous system lesions in patients with AIDS. J Nucl Med 1993;34(4):567-575.

• 39. Heald AE, Hoffman JM, Bartlett JA, et al. Differentiation of central nervous system lesions in AIDS patients using positron emission tomography (PET). Int J STD AIDS 1996;7(5):337.

• 40. Santiago JF, Jana S, Gilbert HM, et al. Role of fluorine-18-fluorodeoxyglucose in the work-up of febrile AIDS patients: experience with dual head coincidence imaging. Clinical Positron Imaging 1999;2(6):301-309.

• 41. Rohde H, Horstkotte MA, Loeper S, et al. Recurrent Listeria monocytogenes aortic graft infection: confirmation of relapse by molecular subtyping. Diagn Microbiol Infect Dis 2004;48(1):63-67.

• 42. Krupnick AS, Lombardi JV, Engels FH, et al. 18-fluorodeoxyglucose positron emission tomography as a novel imaging tool for the diagnosis of aortoenteric fistula and aortic graft infection-a case report. Vasc Endovascular Surg 2003;37(5):363-366.

• 43. Fukuchi K, Ishida Y, Higashi M, et al. Detection of aortic graft infection by fluorodeoxyglucose positron emission tomography: comparison with computed tomographic findings. J Vasc Surg 2005;42(5):919-925.

• 44. Keidar Z, Engel A, Nitecki S, et al. PET/CT using 2-deoxy-2-[18F]fluoro-D-glucose for the evaluation of suspected infected vascular graft. Mol Imaging Biol 2003;5(1):23-25.

• 45. Ozsahin H, von Planta M, Muller I, et al. Successful treatment of invasive aspergillosis in chronic granulomatous disease by bone marrow transplantation, granulocyte colony-stimulating factor-mobilized granulocytes, and liposomal amphotericin-B. Blood 1998;92(8):2719-2724.

• 46. Bleeker-Rovers CP, de Sevaux RG, van Hamersvelt HW, et al. Diagnosis of renal and hepatic cyst infections by 18-F-fluorodeoxyglucose positron emission tomography in autosomal dominant polycystic kidney disease. Am J Kidney Dis 2003;41(6):E18-21.

• 47. Bleeker-Rovers CP, Warris A, Drenth JP, et al. Diagnosis of Candida lung abscesses by 18F-fluorodeoxyglucose positron emission tomography. Clin Microbiol Infect 2005;11(6):493-495.

• 48. Win Z, Todd J, Al-Nahhas A. FDG-PET imaging in Pneumocystis carinii pneumonia. Clin Nucl Med 2005;30(10):690-691.

• 49. Reuter S, Buck A, Manfras B, et al. Structured treatment interruption in patients with alveolar echinococcosis. Hepatology 2004;39(2):509-517.

• 50. Win Z, O'Flynn E, O'Rourke EJ, et al. F-18 FDG PET in the diagnosis and monitoring of salmonella vertebral osteomyelitis: a comparison with MRI. Clin Nucl Med 2006;31(7):437-440.

• 51. Hakim SG, Bruecker CW, Jacobsen H, et al. The value of FDG-PET and bone scintigraphy with SPECT in the primary diagnosis and follow-up of patients with chronic osteomyelitis of the mandible. Int J Oral Maxillofac Surg 2006;35(9):809-816.

Dr. Basu is an ACSBI fellow, and Dr. Alavi is the emeritus nuclear medicine chair, both at the Hospital of the University of Pennsylvania in Philadelphia.