18F-Fluorodeoxyglucose Positron Emission Tomography Contributes to the Diagnosis and Management of Infections in Patients With Multiple Myel
http://www.100md.com
《临床肿瘤学》
the University of Arkansas for Medical Sciences, Myeloma Institute for Research and Therapy, and the Department of Radiology, Little Rock, AR
ABSTRACT
PURPOSE: Correctly identifying infection in cancer patients can be challenging. Limited data suggest that positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) may be useful for diagnosing infection. To determine the role of FDG-PET in the diagnosis of infection in patients with multiple myeloma (MM).
PATIENTS AND METHODS: The medical records of 248 patients who had FDG-PET performed for MM staging or infection work-up revealing increased uptake at extramedullary sites and/or bones and joints that would be atypical for MM between October 2001 and May 2004 were reviewed to identify infections and evaluate FDG-PET contribution to patient outcome.
RESULTS: One hundred sixty-five infections were identified in 143 adults with MM. Infections involved the respiratory tract [99; pneumonia (93), sinusitis (six)], bone, joint and soft tissues [26; discitis (10), osteomyelitis (nine), septic arthritis (one), cellulitis (six)], vascular system [18; septic thrombophlebitis (nine), infection of implantable catheter (eight), septic emboli (one)], gastrointestinal tract [12; colitis (seven), abdominal abscess (three), and diverticulitis and esophagitis (one each)], and dentition [periodontal abscess (10)]. Infections were caused by bacteria, mycobacteria, fungi, and viruses. FDG-PET detected infection even in patients with severe neutropenia and lymphopenia (30 episodes). The FDG-PET findings identified infections not detectable by other methods (46 episodes), determined extent of infection (32 episodes), and led to modification of work-up and therapy (55 episodes). Twenty silent, but clinically relevant, infections were detected among patients undergoing staging FDG-PET.
CONCLUSION: In patients with MM, FDG-PET is a useful tool for diagnosing and managing infections even in the setting of severe immunosuppression.
INTRODUCTION
Infection continues to represent a diagnostic and therapeutic challenge in the management of immunosuppressed patients with hematologic malignancies1 in whom timely diagnosis and treatment is often delayed because of the absence of the typical manifestations of infection.1,2
Fluorine-18 fluorodeoxyglucose (FDG) accumulates in metabolically active cells, including neoplastic and inflammatory cells, and FDG–positron emission tomography (PET) is useful in detecting malignant, inflammatory, and infectious conditions3-7 and may represent a potentially important tool for the diagnosis of infection in patients with hematologic cancer.
We herein describe the first series of FDG-PET scans for the diagnosis of infection in patients with multiple myeloma (MM) and determine the clinical contribution of this test.
PATIENTS AND METHODS
The study was conducted at the Myeloma Institute for Research and Therapy, The University of Arkansas for Medical Sciences, Little Rock, Arkansas, and was approved by the institutional review board (IRB). Imaging studies have been performed as part of an IRB-approved investigational study.
October 1, 2001 to May 31, 2004, 2,631 FDG-PET scans were performed in 1,110 patients with MM either for cancer staging and/or for the diagnosis of suspected infection. The medical records of the 248 patients with MM whose FDG-PET scan was reported as showing increased radiotracer uptake at extramedullary sites and/or bone and joint lesions that would be atypical for MM were reviewed to identify cases associated with infection. Atypical bone and joint lesions included crossing the disk space, patterns suggestive of pus tracts, abnormal isotope uptake following a joint capsule distribution or crossing of a joint space, isotope uptake associated with an orthopedic hardware, including joint replacements, and so on.3
Definitions
Infection was defined according to the criteria of the Centers for Disease Control and Prevention.8 Previously published criteria were used for the diagnosis of septic thrombophlebitis.9 Neutropenia, lymphopenia, and Cluster designation-4 helper T-cell count (CD4) lymphopenia were defined as an absolute neutrophil count, absolute lymphocyte count, and absolute CD4 cell count of less than 1,000 cells/μL, less than 1,000 cells/μL, and less than 500 cells/μL, respectively. Severe immunosuppression was defined as an absolute neutrophil count, absolute lymphocyte count, or CD4 counts of less than 100 cells/μL.
Diagnostic work-up for infection. Conventional diagnostic tests for infection were performed in all patients prior to or at the time of PET scanning and included routine laboratory tests (ie, CBC, chemistry, C-reactive protein, cultures [blood, urine, others as indicated]), serology, chest radiography or computed tomography (CT), and magnetic resonance imaging (MRI) scans. Additional diagnostic tests such as abdomen and pelvis CT, bronchoalveolar lavage, endoscopy and tissue biopsies, and others were performed as clinically indicated. Infection was suspected when a combination of several of the following were present: fever and/or signs and symptoms of sepsis, presence of localizing symptoms, leukocytosis, elevated C-reactive protein, and others.8
Silent infection was considered to be present when abnormal FDG uptake was present in a patient who did not exhibit signs and/or symptoms of infection at the time of the staging PET scan and in whom (1) diagnostic work-up established the presence of infection at the site of abnormal FDG uptake, or (2) no action was taken at the time of the staging PET scan and the patient subsequently developed signs and symptoms of infection at the site of abnormal FDG uptake.
Except for episodes of disseminated infection (eg, septic thrombophlebitis with septic pulmonary emboli), each organ infection was considered as an independent episode (eg, Clostridium difficile colitis and concomitant pneumonia).
FDG-PET imaging. Whole-body imaging was done on a GE Advance NXI Whole Body PET scanner (GE Medical Systems, Milwaukee, WI) in accordance with the manufacturer’s guidelines, beginning 1 hour following injection of FDG IV. Imaging was done from hips to vertex with 4 minutes per bed position and from hips to feet with 2 minute bed positions. Attenuation correction of the upper body only was performed with germanium source rods after emission imaging, using measured, nonsegmented attenuation. Image reconstruction was performed with 2D Ordered Subsets-Expectation Maximum (OS-EM) using iterative reconstructions with two iterations, using a Hanning filter with a 7-mm cutoff.
Standardized uptake values (SUV) for body weight were calculated according to the standard formula.
Patient data. The medical records of all patients were reviewed to determine the presence and type of infection and the contribution of FDG-PET scan to patient management.
The FDG-PET scan was considered contributory when it resulted in any of the following:
Identification of the presence and site of infection (other conventional tests performed at the time of PET imaging were negative and/or noncontributory to the diagnosis of infection);
Determination of the extent of the infection (defined by the number and size of lesions in a specific organ, involvement of other organs, and so on); and
Modification of diagnostic work-up and/or therapy such as targeted diagnostic procedure, removal of infection site (device, tooth extraction, surgical debridement, and so on), and/or change in the duration of antibiotic therapy.
Statistical Methods
Simple student’s t test was used to compare the actual difference between two means in relation to the variation in the data (expressed as the standard deviation of the difference between the means). SAS version 8.0 (SAS Institute Inc, Cary, NC) was used for statistical analysis. Statistical significance was defined as .05.
RESULTS
Patient Distribution
Two hundred forty-eight patients whose FDG-PET scan showed increased uptake at extramedullary sites and/or bone and joint lesions were identified (Fig 1).
Infectious Episodes
A total of 165 infectious episodes were identified in 143 adult patients with MM. One hundred ten infectious episodes were detected among the 94 myeloma patients who had FDG-PET obtained for cancer staging; 20 of them (18%) were clinically silent. The remaining 55 infectious episodes were identified among 49 patients who had undergone FDG-PET for diagnosis of infection (33%).
Ninety-one patients were male and the mean age was 58 years (range, 32 to 76 years). Seventy patients were in remission. Among the 73 patients who had received antineoplastic therapy during the month preceding PET scanning, 40 had undergone myeloablative chemotherapy with autologous peripheral stem-cell transplant. Immunosuppression was present during most infectious episodes and included neutropenia, lymphopenia, and/or CD4 lymphopenia (27 episodes, 98 episodes, and 96 episodes, respectively) and was severe in 30 episodes.
Infections involved the respiratory tract (99; pneumonia [93], sinusitis [6]), bone, joint, and soft tissues (26; discitis [10], osteomyelitis [nine], septic arthritis [one], cellulitis [six]), the vascular system (18; septic thrombophlebitis [nine], infection of implantable catheter [eight], septic emboli [one]), the gastrointestinal tract (12; colitis [seven], diverticulitis and esophagitis [one each], and abdominal abscess [three]), dentition (periodontal abscess [10]). Some of the episodes of vascular infection were previously reported by us.9,10
Fifty-seven of the 165 infections (34%) were documented either by microbiology (36 infections), histopathology (nine infections), or both (11 infections). Infections were caused by various pathogens (Fig 2).
The intensity of FDG uptake (as measured by the mean of maximum SUV) for the 165 episodes was 6.07 (range, 0.8 to 22.1). No difference was found between the maximum SUV of the 30 episodes that developed during severe immunosuppression (mean maximum SUV, 5.75; range, 0.8 to 12) and the 30 episodes not associated with immunosuppression (mean maximum SUV, 5.92; range, 2.4 to 22.1; P = .866).
FDG-PET scan contributed to patient management in 76 episodes (46%; Table 1, Fig 3), particularly for infections involving the vascular system or bones and joints. The contribution of FDG-PET to management included: (a) identification of the presence and site of infection (46 episodes); (b) determination of the extent of the infection (32 episodes); and (c) modification of the diagnostic work-up and therapy (55 episodes).
In addition, 69 of the 143 MM patients underwent follow-up FDG-PET (76 scans) for cancer staging, which allowed us to retrospectively assess the potential usefulness of FDG-PET for evaluating infection response to therapy. Mean time from start of antibiotic treatment to follow-up FDG-PET was 102 days (range, 11 to 711 days). Resolution of abnormal uptake at sites of prior infection was observed in 67 of the follow-up FDG-PET scans (88%) together with resolution of signs and symptoms and laboratory markers of infection. A total of 22 patients had a routine test (CT or MRI) done concomitant with follow-up PET. Seventeen of these 22 patients had pneumonia and concurrent follow-up PET and CT done between 30 days and 90 days after start of antibiotic therapy. The follow-up PET showed resolution in 16 of these patients, who also had clinical resolution of all signs and symptoms of pneumonia; one patient, who had a 50% decrease in the SUV of the pulmonary lesions but without a change in their number, continued to have clinical evidence of pneumonia and his follow-up CT was still positive for concordant pulmonary infiltrates. Concurrent CT findings in the other 16 patients showed resolution in nine patients, improvement in three patients, and persistent changes in four patients. These persistent CT changes without uptake on the concurrent PET likely represent scarring.
Three patients with diskitis, septic pulmonary emboli, and colitis (1 each) had concurrent follow-up PET and CT after treatment, showing resolution by both methods at 54 days, 59 days, and 140 days, respectively. In addition, two patients with chronic osteomyelitis showed persistent abnormalities by concurrent PET and MRI 71 and 122 days after of starting antibiotic therapy, respectively.
DISCUSSION
This report describes the first study of the role of FDG-PET in the diagnosis and management of infection in patients with hematologic cancer and suggests that FDG-PET may play an important role in this setting. Several new findings have emerged from our study, including the ability of FDG-PET to: (a) detect infectious foci not identified with conventional diagnostic methods; (b) determine the extent of infection; and (c) lead to modifications in the diagnostic and therapeutic strategy. Additional new findings include the ability of FDG-PET to detect infections in the presence of severe immunosuppression and to identify clinically silent infections in patients undergoing FDG-PET staging of their underlying disease. Our data also suggest that FDG-PET scan might be useful to monitor response to infection. However, the long mean time (102 days) between the original and follow-up scan limits our ability to evaluate the true usefulness of this test to monitor infection response. In clinical practice, FDG-PET should not be routinely utilized for this purpose but rather be limited to select clinical settings such as when conventional imaging suggests persistent abnormalities before resumption of immunosuppressive antineoplastic therapy. Additional studies are needed to address the role of FDG-PET in this setting.
Our results are supported by a limited number of reports describing the clinical usefulness of FDG-PET in the diagnosis of infections in other patient populations.7,11-17 As previously reported by us,9,10 FDG-PET scan can be particularly useful for the diagnosis of vascular infections such as septic thrombophlebitis and infections of implantable catheters.
Other nuclear imaging techniques also play a significant role in the diagnosis of infection including 111 Indium or 99m Technetium labeled WBC scans, and Gallium scans.18 Compared with these techniques, FDG-PET scan provides earlier diagnosis (< 1 hour v 4 to 24 hours), is less labor-intensive, and utilizes a shorter half-life radiotracer (< 2 hours v 6 to 67 hours).19 Unlike most other nuclear imaging techniques, FDG-PET scan can be diagnostic in the setting of severe neutropenia and is also useful for staging the underlying cancer.20 The sometimes difficult spatial localization of the FDG-PET scan has now been overcome by the introduction of dual-modality FDG-PET/CT.20
Our study is limited by the relatively small number of infectious episodes at anatomic sites other than lungs and the nonsimultaneous imaging with various techniques. A prospective, larger study is currently ongoing to confirm our preliminary findings and address some of these limitations. Another potential limitation of FDG-PET for diagnosing infections is the inability of the test to discriminate between infection and malignancy. This is unlikely to represent a problem for infections at sites not usually involved by cancer (ie, vascular infections, dental abscesses, sinusitis, discitis, and septic arthritis) and for patients with malignancies unlikely to involve certain organs. Because MM does not usually involve the respiratory or gastrointestinal tract, abnormal uptake of FDG-PET at these sites should raise suspicions for infection, leading to additional infection-related work-up. By contrast, this limitation is likely to be clinically relevant when evaluating malignancies known to involve the respiratory or gastro-intestinal tract such as lung, colon, or breast cancer. Response of the underlying disease using nonradiologic parameters (ie, clinical examination, serum markers, bone marrow aspirate and biopsy, and others) would be of great assistance in assessing abnormal FDG-PET uptake at these extramedullary sites. In our report, FDG-PET scan was used as part of an IRB-approved investigational study and not part of routine clinical practice.
Our findings suggest that FDG-PET scan should be considered in immunosuppressed patients with suspected infection and a negative diagnostic work-up and in those with a recently treated infection but persistent findings by conventional radiologic tests. In the latter setting, a negative FDG-PET scan, in the absence of other clinical or laboratory markers for infection, would suggest resolution of the infection, hence, allowing safe initiation of chemotherapy. We have also previously demonstrated that FDG-PET diagnoses vascular infections, including septic thrombophlebitis and infections of implantable catheters.9,10 Thus, FDG-PET should be considered when an intravascular infection is suspected. Finally, increased uptake at extramedullary sites on staging FDG-PET should prompt a work-up for infection. This is particularly important when the increased uptake is noted at sites not typically involved by the underlying disease. Treating these infections before commencing antineoplastic therapy is critical to avoid potentially devastating consequences.
In conclusion, FDG-PET scan appears to be a rapid and reliable tool for the diagnosis and management of infections in patients with MM, including those with severe immunosuppression.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
O’Brien SN, Blijlevens NM, Mahfouz TH, et al: Infections in patients with hematological cancer: Recent developments. Hematology (Am Soc Hematol Educ Program) 438-472, 2003
Crawford J, Dale DC, Lyman GH: Chemotherapy-induced neutropenia: Risks, consequences, and new directions for its management. Cancer 100:228-237, 2004
Sugawara Y: Infection and inflammation, in Wahl R, Buchanam J (eds): Principles and Practice of Positron Emission Tomography (ed 1st). Philadelphia, PA, Lippincott Williams & Wilkins, 2002, pp 381-394
Stumpe KD, Dazzi H, Schaffner A, et al: Infection imaging using whole-body FDG-PET. Eur J Nucl Med 27:822-832, 2000
Zhuang H, Alavi A: 18-Fluorodeoxyglucose positron emission tomographic imaging in the detection and monitoring of infection and inflammation. Semin Nucl Med 32:47-59, 2002
Rennen H, Boerman O, Oyen W, et al: Imaging infection /inflammation in the new millennium. Eur J Nucl Med 28:241-252, 2001
De Winter F, Vogelaers D, Gemmel F, et al: Promising role of 18-F-fluoro-D-Deoxyglucose positron emission tomography in clinical infectious diseases. Eur J Clin Microbiol Infect Dis 21:247-257, 2002
Garner JS, Jarvis WR, Emori TG, et al: CDC definitions for nosocomial infections. Am J Infect Control 16:128-140, 1988
Miceli M, Atoui R, Walker R, et al: Diagnosis of deep septic thrombophlebitis in cancer patients by fluorine-18 fluorodeoxyglucose positron emission tomography scanning: A preliminary report. J Clin Oncol 22:1949-1956, 2004
Miceli M, Jones-Jackson L, Walker R, et al: Diagnosis of infection of implantable central venous catheters by fluorine-18 fluorodeoxyglucose positron emission tomography. Nucl Med Com 25:813-818, 2004
Franzius C, Biermann M, Hulskamp G, et al: Therapy monitoring in aspergillosis using F-18 FDG positron emission tomography. Clin Nucl Med 26:232-233, 2001
Goswami GK, Jana S, Santiago JF, et al: Discrepancy between Ga-67 citrate and F-18 fluorodeoxyglucose positron emission tomographic scans in pulmonary infection. Clin Nucl Med 25:490-491, 2000
Goo JM, Im JG, Do KH, et al: Pulmonary tuberculoma evaluated by means of FDG PET: Findings in 10 cases. Radiology 216:117-121, 2000
Muller AE, Kluge R, Biesold M, et al: Whole body positron emission tomography detected occult infectious foci in a child with acute myeloid leukaemia. Med Pediatr Oncol 38:58-59, 2002
Tahara T, Ichiya Y, Kuwabara Y, et al: High [18F]-fluorodeoxyglucose uptake in abdominal abscesses: A PET study. J Comput Assist Tomogr 13:829-831, 1989
Gungor T, Engel-Bicik I, Eich G, et al: Diagnostic and therapeutic impact of whole body positron emission tomography using fluorine-18-fluoro-2-deoxy-D-glucose in children with chronic granulomatous disease. Arch Dis Child 85:341-345, 2001
Bleeker-Rovers CP, de Kleijn EM, Corstens FH, et al: Clinical value of FDG PET in patients with fever of unknown origin and patients suspected of focal infection or inflammation. Eur J Nucl Med Mol Imaging 31:29-37, 2004
Gibel LJ, Hartshorne MF, Tzamaloukas AH: Indium-111 oxine leukocyte scan in the diagnosis of peritoneal catheter tunnel infections. Perit Dial Int 18:234-235, 1998
Mettler F, Guiberteau M: Inflammation and Infection Imaging, in Mettler F (ed): Essentials of Nuclear Medicine Imaging (ed 4th). Philadelphia, PA, W.B. Saunders Company, 1998, pp 387-403
Wahl R: Principles of Cancer Imaging with Fluorodeoxyglucose, in Wahl R (ed): Positron Emission Tomography (ed 1). Philadelphia, PA, Lippincott Williams & Wilkins, 2002, pp 100-110(T. Mahfouz, M.H. Miceli, )
ABSTRACT
PURPOSE: Correctly identifying infection in cancer patients can be challenging. Limited data suggest that positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) may be useful for diagnosing infection. To determine the role of FDG-PET in the diagnosis of infection in patients with multiple myeloma (MM).
PATIENTS AND METHODS: The medical records of 248 patients who had FDG-PET performed for MM staging or infection work-up revealing increased uptake at extramedullary sites and/or bones and joints that would be atypical for MM between October 2001 and May 2004 were reviewed to identify infections and evaluate FDG-PET contribution to patient outcome.
RESULTS: One hundred sixty-five infections were identified in 143 adults with MM. Infections involved the respiratory tract [99; pneumonia (93), sinusitis (six)], bone, joint and soft tissues [26; discitis (10), osteomyelitis (nine), septic arthritis (one), cellulitis (six)], vascular system [18; septic thrombophlebitis (nine), infection of implantable catheter (eight), septic emboli (one)], gastrointestinal tract [12; colitis (seven), abdominal abscess (three), and diverticulitis and esophagitis (one each)], and dentition [periodontal abscess (10)]. Infections were caused by bacteria, mycobacteria, fungi, and viruses. FDG-PET detected infection even in patients with severe neutropenia and lymphopenia (30 episodes). The FDG-PET findings identified infections not detectable by other methods (46 episodes), determined extent of infection (32 episodes), and led to modification of work-up and therapy (55 episodes). Twenty silent, but clinically relevant, infections were detected among patients undergoing staging FDG-PET.
CONCLUSION: In patients with MM, FDG-PET is a useful tool for diagnosing and managing infections even in the setting of severe immunosuppression.
INTRODUCTION
Infection continues to represent a diagnostic and therapeutic challenge in the management of immunosuppressed patients with hematologic malignancies1 in whom timely diagnosis and treatment is often delayed because of the absence of the typical manifestations of infection.1,2
Fluorine-18 fluorodeoxyglucose (FDG) accumulates in metabolically active cells, including neoplastic and inflammatory cells, and FDG–positron emission tomography (PET) is useful in detecting malignant, inflammatory, and infectious conditions3-7 and may represent a potentially important tool for the diagnosis of infection in patients with hematologic cancer.
We herein describe the first series of FDG-PET scans for the diagnosis of infection in patients with multiple myeloma (MM) and determine the clinical contribution of this test.
PATIENTS AND METHODS
The study was conducted at the Myeloma Institute for Research and Therapy, The University of Arkansas for Medical Sciences, Little Rock, Arkansas, and was approved by the institutional review board (IRB). Imaging studies have been performed as part of an IRB-approved investigational study.
October 1, 2001 to May 31, 2004, 2,631 FDG-PET scans were performed in 1,110 patients with MM either for cancer staging and/or for the diagnosis of suspected infection. The medical records of the 248 patients with MM whose FDG-PET scan was reported as showing increased radiotracer uptake at extramedullary sites and/or bone and joint lesions that would be atypical for MM were reviewed to identify cases associated with infection. Atypical bone and joint lesions included crossing the disk space, patterns suggestive of pus tracts, abnormal isotope uptake following a joint capsule distribution or crossing of a joint space, isotope uptake associated with an orthopedic hardware, including joint replacements, and so on.3
Definitions
Infection was defined according to the criteria of the Centers for Disease Control and Prevention.8 Previously published criteria were used for the diagnosis of septic thrombophlebitis.9 Neutropenia, lymphopenia, and Cluster designation-4 helper T-cell count (CD4) lymphopenia were defined as an absolute neutrophil count, absolute lymphocyte count, and absolute CD4 cell count of less than 1,000 cells/μL, less than 1,000 cells/μL, and less than 500 cells/μL, respectively. Severe immunosuppression was defined as an absolute neutrophil count, absolute lymphocyte count, or CD4 counts of less than 100 cells/μL.
Diagnostic work-up for infection. Conventional diagnostic tests for infection were performed in all patients prior to or at the time of PET scanning and included routine laboratory tests (ie, CBC, chemistry, C-reactive protein, cultures [blood, urine, others as indicated]), serology, chest radiography or computed tomography (CT), and magnetic resonance imaging (MRI) scans. Additional diagnostic tests such as abdomen and pelvis CT, bronchoalveolar lavage, endoscopy and tissue biopsies, and others were performed as clinically indicated. Infection was suspected when a combination of several of the following were present: fever and/or signs and symptoms of sepsis, presence of localizing symptoms, leukocytosis, elevated C-reactive protein, and others.8
Silent infection was considered to be present when abnormal FDG uptake was present in a patient who did not exhibit signs and/or symptoms of infection at the time of the staging PET scan and in whom (1) diagnostic work-up established the presence of infection at the site of abnormal FDG uptake, or (2) no action was taken at the time of the staging PET scan and the patient subsequently developed signs and symptoms of infection at the site of abnormal FDG uptake.
Except for episodes of disseminated infection (eg, septic thrombophlebitis with septic pulmonary emboli), each organ infection was considered as an independent episode (eg, Clostridium difficile colitis and concomitant pneumonia).
FDG-PET imaging. Whole-body imaging was done on a GE Advance NXI Whole Body PET scanner (GE Medical Systems, Milwaukee, WI) in accordance with the manufacturer’s guidelines, beginning 1 hour following injection of FDG IV. Imaging was done from hips to vertex with 4 minutes per bed position and from hips to feet with 2 minute bed positions. Attenuation correction of the upper body only was performed with germanium source rods after emission imaging, using measured, nonsegmented attenuation. Image reconstruction was performed with 2D Ordered Subsets-Expectation Maximum (OS-EM) using iterative reconstructions with two iterations, using a Hanning filter with a 7-mm cutoff.
Standardized uptake values (SUV) for body weight were calculated according to the standard formula.
Patient data. The medical records of all patients were reviewed to determine the presence and type of infection and the contribution of FDG-PET scan to patient management.
The FDG-PET scan was considered contributory when it resulted in any of the following:
Identification of the presence and site of infection (other conventional tests performed at the time of PET imaging were negative and/or noncontributory to the diagnosis of infection);
Determination of the extent of the infection (defined by the number and size of lesions in a specific organ, involvement of other organs, and so on); and
Modification of diagnostic work-up and/or therapy such as targeted diagnostic procedure, removal of infection site (device, tooth extraction, surgical debridement, and so on), and/or change in the duration of antibiotic therapy.
Statistical Methods
Simple student’s t test was used to compare the actual difference between two means in relation to the variation in the data (expressed as the standard deviation of the difference between the means). SAS version 8.0 (SAS Institute Inc, Cary, NC) was used for statistical analysis. Statistical significance was defined as .05.
RESULTS
Patient Distribution
Two hundred forty-eight patients whose FDG-PET scan showed increased uptake at extramedullary sites and/or bone and joint lesions were identified (Fig 1).
Infectious Episodes
A total of 165 infectious episodes were identified in 143 adult patients with MM. One hundred ten infectious episodes were detected among the 94 myeloma patients who had FDG-PET obtained for cancer staging; 20 of them (18%) were clinically silent. The remaining 55 infectious episodes were identified among 49 patients who had undergone FDG-PET for diagnosis of infection (33%).
Ninety-one patients were male and the mean age was 58 years (range, 32 to 76 years). Seventy patients were in remission. Among the 73 patients who had received antineoplastic therapy during the month preceding PET scanning, 40 had undergone myeloablative chemotherapy with autologous peripheral stem-cell transplant. Immunosuppression was present during most infectious episodes and included neutropenia, lymphopenia, and/or CD4 lymphopenia (27 episodes, 98 episodes, and 96 episodes, respectively) and was severe in 30 episodes.
Infections involved the respiratory tract (99; pneumonia [93], sinusitis [6]), bone, joint, and soft tissues (26; discitis [10], osteomyelitis [nine], septic arthritis [one], cellulitis [six]), the vascular system (18; septic thrombophlebitis [nine], infection of implantable catheter [eight], septic emboli [one]), the gastrointestinal tract (12; colitis [seven], diverticulitis and esophagitis [one each], and abdominal abscess [three]), dentition (periodontal abscess [10]). Some of the episodes of vascular infection were previously reported by us.9,10
Fifty-seven of the 165 infections (34%) were documented either by microbiology (36 infections), histopathology (nine infections), or both (11 infections). Infections were caused by various pathogens (Fig 2).
The intensity of FDG uptake (as measured by the mean of maximum SUV) for the 165 episodes was 6.07 (range, 0.8 to 22.1). No difference was found between the maximum SUV of the 30 episodes that developed during severe immunosuppression (mean maximum SUV, 5.75; range, 0.8 to 12) and the 30 episodes not associated with immunosuppression (mean maximum SUV, 5.92; range, 2.4 to 22.1; P = .866).
FDG-PET scan contributed to patient management in 76 episodes (46%; Table 1, Fig 3), particularly for infections involving the vascular system or bones and joints. The contribution of FDG-PET to management included: (a) identification of the presence and site of infection (46 episodes); (b) determination of the extent of the infection (32 episodes); and (c) modification of the diagnostic work-up and therapy (55 episodes).
In addition, 69 of the 143 MM patients underwent follow-up FDG-PET (76 scans) for cancer staging, which allowed us to retrospectively assess the potential usefulness of FDG-PET for evaluating infection response to therapy. Mean time from start of antibiotic treatment to follow-up FDG-PET was 102 days (range, 11 to 711 days). Resolution of abnormal uptake at sites of prior infection was observed in 67 of the follow-up FDG-PET scans (88%) together with resolution of signs and symptoms and laboratory markers of infection. A total of 22 patients had a routine test (CT or MRI) done concomitant with follow-up PET. Seventeen of these 22 patients had pneumonia and concurrent follow-up PET and CT done between 30 days and 90 days after start of antibiotic therapy. The follow-up PET showed resolution in 16 of these patients, who also had clinical resolution of all signs and symptoms of pneumonia; one patient, who had a 50% decrease in the SUV of the pulmonary lesions but without a change in their number, continued to have clinical evidence of pneumonia and his follow-up CT was still positive for concordant pulmonary infiltrates. Concurrent CT findings in the other 16 patients showed resolution in nine patients, improvement in three patients, and persistent changes in four patients. These persistent CT changes without uptake on the concurrent PET likely represent scarring.
Three patients with diskitis, septic pulmonary emboli, and colitis (1 each) had concurrent follow-up PET and CT after treatment, showing resolution by both methods at 54 days, 59 days, and 140 days, respectively. In addition, two patients with chronic osteomyelitis showed persistent abnormalities by concurrent PET and MRI 71 and 122 days after of starting antibiotic therapy, respectively.
DISCUSSION
This report describes the first study of the role of FDG-PET in the diagnosis and management of infection in patients with hematologic cancer and suggests that FDG-PET may play an important role in this setting. Several new findings have emerged from our study, including the ability of FDG-PET to: (a) detect infectious foci not identified with conventional diagnostic methods; (b) determine the extent of infection; and (c) lead to modifications in the diagnostic and therapeutic strategy. Additional new findings include the ability of FDG-PET to detect infections in the presence of severe immunosuppression and to identify clinically silent infections in patients undergoing FDG-PET staging of their underlying disease. Our data also suggest that FDG-PET scan might be useful to monitor response to infection. However, the long mean time (102 days) between the original and follow-up scan limits our ability to evaluate the true usefulness of this test to monitor infection response. In clinical practice, FDG-PET should not be routinely utilized for this purpose but rather be limited to select clinical settings such as when conventional imaging suggests persistent abnormalities before resumption of immunosuppressive antineoplastic therapy. Additional studies are needed to address the role of FDG-PET in this setting.
Our results are supported by a limited number of reports describing the clinical usefulness of FDG-PET in the diagnosis of infections in other patient populations.7,11-17 As previously reported by us,9,10 FDG-PET scan can be particularly useful for the diagnosis of vascular infections such as septic thrombophlebitis and infections of implantable catheters.
Other nuclear imaging techniques also play a significant role in the diagnosis of infection including 111 Indium or 99m Technetium labeled WBC scans, and Gallium scans.18 Compared with these techniques, FDG-PET scan provides earlier diagnosis (< 1 hour v 4 to 24 hours), is less labor-intensive, and utilizes a shorter half-life radiotracer (< 2 hours v 6 to 67 hours).19 Unlike most other nuclear imaging techniques, FDG-PET scan can be diagnostic in the setting of severe neutropenia and is also useful for staging the underlying cancer.20 The sometimes difficult spatial localization of the FDG-PET scan has now been overcome by the introduction of dual-modality FDG-PET/CT.20
Our study is limited by the relatively small number of infectious episodes at anatomic sites other than lungs and the nonsimultaneous imaging with various techniques. A prospective, larger study is currently ongoing to confirm our preliminary findings and address some of these limitations. Another potential limitation of FDG-PET for diagnosing infections is the inability of the test to discriminate between infection and malignancy. This is unlikely to represent a problem for infections at sites not usually involved by cancer (ie, vascular infections, dental abscesses, sinusitis, discitis, and septic arthritis) and for patients with malignancies unlikely to involve certain organs. Because MM does not usually involve the respiratory or gastrointestinal tract, abnormal uptake of FDG-PET at these sites should raise suspicions for infection, leading to additional infection-related work-up. By contrast, this limitation is likely to be clinically relevant when evaluating malignancies known to involve the respiratory or gastro-intestinal tract such as lung, colon, or breast cancer. Response of the underlying disease using nonradiologic parameters (ie, clinical examination, serum markers, bone marrow aspirate and biopsy, and others) would be of great assistance in assessing abnormal FDG-PET uptake at these extramedullary sites. In our report, FDG-PET scan was used as part of an IRB-approved investigational study and not part of routine clinical practice.
Our findings suggest that FDG-PET scan should be considered in immunosuppressed patients with suspected infection and a negative diagnostic work-up and in those with a recently treated infection but persistent findings by conventional radiologic tests. In the latter setting, a negative FDG-PET scan, in the absence of other clinical or laboratory markers for infection, would suggest resolution of the infection, hence, allowing safe initiation of chemotherapy. We have also previously demonstrated that FDG-PET diagnoses vascular infections, including septic thrombophlebitis and infections of implantable catheters.9,10 Thus, FDG-PET should be considered when an intravascular infection is suspected. Finally, increased uptake at extramedullary sites on staging FDG-PET should prompt a work-up for infection. This is particularly important when the increased uptake is noted at sites not typically involved by the underlying disease. Treating these infections before commencing antineoplastic therapy is critical to avoid potentially devastating consequences.
In conclusion, FDG-PET scan appears to be a rapid and reliable tool for the diagnosis and management of infections in patients with MM, including those with severe immunosuppression.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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