Nuclear Medicine Imaging Tools in Fever of Unknown Origin: Time for a Revisit and Appropriate Use Criteria.

Fever of unknown origin (FUO) is a clinical conundrum for patients and clinicians alike, and imaging studies are often performed as part of the diagnostic workup of these patients. Recently, the Society of Nuclear Medicine and Molecular Imaging convened and approved a guideline on the use of nuclear medicine tools for FUO. The guidelines support the use of 2-18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in adults and children with FUO. 18F-FDG PET/CT allows detection and localization of foci of hypermetabolic lesions with high sensitivity because of the 18F-FDG uptake in glycolytically active cells that may represent inflammation, infection, or neoplasia. Clinicians should consider and insurers should cover 18F-FDG PET/CT when evaluating patients with FUO, particularly when other clinical clues and preliminary studies are unrevealing.

FDG-PET/CT for investigation of pyrexia of unknown origin: a cost of illness analysis.

BACKGROUND: Our study aims to explore the current utilisation of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in the diagnostic pathway of pyrexia of unknown origin (PUO) and associated cost of illness in a large tertiary teaching hospital in Australia. METHOD: 1257 febrile patients between June 2016 and September 2022 were retrospectively reviewed. There were 57 patients who met the inclusion criteria of "classical PUO", of which FDG-PET/CT was performed in 31 inpatients, 15 outpatients and 11 inpatients did not have an FDG-PET/CT scan. The patient demographics, clinical characteristics and inpatient cost were analysed, together with the diagnostic performance of FDG-PET/CT and impact on clinical management. RESULT: The mean age, length of stay and total cost of admission were higher for inpatients who received FDG-PET/CT versus those who did not. The median cost per patient-bed-day did not differ between the two groups. Inpatients who received earlier FDG-PET/CTs (≤ 7 days from admission) had shorter length of stays and lower total cost compared to those who received a later scan. A negative FDG-PET/CT scan, demonstrating no serious or life-threatening abnormalities resulted in subsequent discharge from hospital or outpatient clinic in 7/10 (70%) patients. There were 11/40 (28%) scans where ancillary abnormalities were identified, requiring further evaluation. CONCLUSION: FDG-PET/CT showed high diagnostic accuracy and significant impact on patient management in patients with PUO. FDG-PET/CT performed earlier in admission for PUO was associated with shorter length of stay and lower total cost.

EANM consensus document on the use of [18F]FDG PET/CT in fever and inflammation of unknown origin.

PURPOSE: Patients with fever and inflammation of unknown origin (FUO/IUO) are clinically challenging due to variable clinical presentations with nonspecific symptoms and many differential diagnoses. Positron emission tomography/computed tomography (PET/CT) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is increasingly used in FUO and IUO, but the optimal diagnostic strategy remains controversial. This consensus document aims to assist clinicians and nuclear medicine specialists in the appropriate use of [18F]FDG-PET/CT in FUO and IUO based on current evidence. METHODS: A working group created by the EANM infection and inflammation committee performed a systematic literature search based on PICOs with "patients with FUO/IUO" as population, "[18F]FDG-PET/CT" as intervention, and several outcomes including pre-scan characteristics, scan protocol, diagnostic yield, impact on management, prognosis, and cost-effectiveness. RESULTS: We included 68 articles published from 2001 to 2023: 9 systematic reviews, 49 original papers on general adult populations, and 10 original papers on specific populations. All papers were analysed and included in the evidence-based recommendations. CONCLUSION: FUO and IUO remains a clinical challenge and [18F]FDG PET/CT has a definite role in the diagnostic pathway with an overall diagnostic yield or helpfulness in 50-60% of patients. A positive scan is often contributory by directly guiding treatment or subsequent diagnostic procedure. However, a negative scan may be equally important by excluding focal disease and predicting a favorable prognosis. Similar results are obtained in specific populations such as ICU-patients, children and HIV-patients.

Fever of unknown origin in pediatrics: role of nuclear medicine.

Fever of unknown origin (FUO) is a debated issue in numerous scientific studies in adult patients with a not jet-defined workflow in a clinical and diagnostic setting. Few works are published about pediatric patients even if FUO represents a challenging, not infrequent scenario in hospital and outpatient recovery. The fever might be the onset symptom of a transient mild infection or the beginning of a more difficult-to-diagnose and serious pathological condition. In the adult workflow 18FDG PET-CT is nowadays playing a relevant role, considering the limited spread of conventional 99mTc-HMPAO-White Blood Cells scintigraphy. It represents a robust tool for diagnosing the eventual site of infection, but it is limited by procedural complexity and long duration, up to 24 hours. The WBC-scintigraphy is also not suitable for children, only for young adults or adolescents, considering the relevant blood sample entity and the procedural risk for sensitive subjects. The most assessed clinical and diagnostic know-how on Pediatric FUO are summarized and a synthetic flow-chard is presented to support the clinical management and to choose the best diagnostic pathway.

FDG PET in Evaluation of Patients With Fever of Unknown Origin: AJR Expert Panel Narrative Review.

Fever of unknown origin (FUO) is a diagnostic challenge, with its cause remaining undiagnosed in approximately half of patients. Nuclear medicine tests typically are performed after a negative or inconclusive initial workup. Gallium-67 citrate and labeled leukocytes were previous mainstays of radionuclide imaging for FUO, although they had limited diagnostic performance. FDG PET/CT has subsequently emerged as the nuclear medicine imaging test of choice, supported by a growing volume of evidence. A positive FDG PET/CT result contributes useful information by identifying potential causes of fever, localizing sites for further evaluation, and guiding further management; a negative result contributes useful information by excluding focal disease as the cause of fever and predicts a favorable prognosis. In 2021, CMS rescinded a prior national noncoverage determination for FDG PET for infection and inflammation, leading to increasing national utilization of FDG PET/CT for FUO workup. This article reviews the current status of the role of FDG PET/CT in the evaluation of patients with FUO. The literature reporting the diagnostic performance and yield of FDG PET/CT in FUO workup is summarized, with comparison with historically used nuclear medicine tests included. Attention is also given to the test's clinical impact; protocol, cost, and radiation considerations; and application in children.

Do statins decrease vascular inflammation in patients at risk for large-vessel vasculitis? A retrospective observational study with FDG-PET/CT in polymyalgia rheumatica, giant cell arteritis and fever of unknown origin.

OBJECTIVES: [18F] Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) can detect the presence of large-vessel vasculitis (LVV) in patients with polymyalgia rheumatica (PMR), giant cell arteritis (GCA) and fever of unknown origin (FUO). The aim of this study was to evaluate whether statins could reduce FDG-PET/CT-assessed vascular inflammation in this group of patients. METHODS: Clinical, demographic, laboratory data, current pharmacological treatments, and cardiovascular risk factors of patients with PMR, GCA and FUO, who underwent FDG-PET/CT, were recorded. FDG uptake was measured at prespecified arterial sites with the mean standardised uptake value (SUV), and with a qualitative visual score, summed up to obtain a total vascular score (TVS). LVV was diagnosed if arterial FDG visual uptake was equal or higher of liver uptake. RESULTS: 129 patients were included (96 with PMR, 16 with GCA, 13 with both PMR and GCA, and 4 with FUO), of whom 75 (58.1%) showed LVV. Twenty out of 129 (15.5%) patients were taking statins. TVS was significantly lower in patients treated with statins (p=0.02), especially in the aorta (p=0.023) and femoral arteries (p=0.027). CONCLUSIONS: Our preliminary results suggest that statins may exert a potential protective role on vascular inflammation in patients with PMR and GCA. Statin use could spuriously decrease FDG uptake of the vessel walls.

Diagnostic performance of 18 F-FDG-PET/CT in inflammation of unknown origin: A clinical series of 317 patients.

BACKGROUND: Inflammation of unknown origin (IUO) is a challenging situation in internal medicine. OBJECTIVES: To describe the final diagnoses in IUO and assess the helpfulness of 18 F-fluorodesoxyglucose positron emission tomography with computerized tomography (18 F-FDG-PET/CT) in the diagnosis strategy. RESULTS: A total of 317 IUO patients with 18 F-FDG-PET/CT were enrolled. A diagnosis was reached in 228 patients: noninfectious inflammatory diseases (NIID) (37.5%), infectious diseases (18.6%), malignancies (7.9%), and non-systemic-inflammatory miscellaneous diseases (7.9%). The two leading causes of NIID were polymyalgia rheumatica and giant cell arteritis. 18 F-FDG-PET/CT results were classified as true positive in 49.8% of patients and contributory in 75.1% of overall IUO patients (after the complete investigation set and a prolonged follow-up). In multivariate analysis, only C-reactive protein minimum level (≥50 mg/L) was associated with the contributory status of 18 F-FDG-PET/CT. CONCLUSION: Within the wide spectrum of IUO underlying diseases, 18 F-FDG-PET/CT is helpful to make a diagnosis and to eliminate inflammatory diseases. Obese patients constitute a specific group needing further studies.

Unexplained fever in children-Benefits and challenges of FDG-PET/CT.

AIM: To explore [fluorine-18]-fluoro-2-deoxy-d-glucose positron-emission-tomography/computed tomography (18 FDG-PET/CT) in patients where standard investigations were non-diagnostic. METHODS: We reviewed medical records of previously healthy children who had 18 FDG-PET/CT performed at Copenhagen University Hospital in 2015-2020 due to unexplained fever. RESULTS: Thirty-five of 819 paediatric 18 FDG-PET/CT were performed due to unexplained fever. The final diagnoses were malignancy (11%), infections (23%), inflammatory diseases (43%) and miscellaneous (26%). 18 FDG-PET/CT was diagnostic in six cases with Takayasu's arteritis, tuberculosis, Langerhans cell histiocytosis and Ewing sarcoma. Sixteen cases had focal 18 FDG-uptake, but 18 FDG-PET/CT could only differentiate malignancy, infection and inflammation in three cases. In six cases with inflammatory diseases and no focal signs, PET/CT was normal except increased non-specific 18 FDG-uptake in bone marrow and spleen in five cases. One case was false positive (suspicion of appendicitis) and two false negative (leukaemia and inflammatory disease). CONCLUSION: 18 FDG-PET/CT was diagnostic, or contributed to the diagnosis, in several children with unexplained fever referred to a tertiary centre. Challenges comprised (i) only increased non-specific 18 FDG-uptake in bone marrow and spleen in half of cases with inflammatory diseases, (ii) no differentiation between complicated infections, malignancy and inflammation in most cases with focal processes and (iii) a small risk of false positive and false negative results.

Quantifying the contribution of 18F-FDG PET to the diagnostic assessment of pediatric patients with fever of unknown origin: a systematic review and meta-analysis.

BACKGROUND: The value of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in the diagnostic assessment of pediatric fever of unknown origin is not known, and evidence from adults is not applicable. OBJECTIVE: To quantify the contribution of 18F-FDG PET to pediatric fever of unknown origin, considering its diagnostic limitations. MATERIALS AND METHODS: We searched PubMed, EMBASE and Cochrane Central Register of Controlled Trials up to Feb. 18, 2021. We included studies on patients with pediatric fever of unknown origin presenting sufficient data to calculate the likelihood of achieving definite diagnosis (based on pathology or clinical follow-up) between those with abnormal PET findings versus those with normal PET findings. We assessed the risk of bias using a modified Newcastle-Ottawa quality assessment scale and quantified the value of PET by pooling the likelihood of achieving definite diagnosis using a random-effects model. RESULTS: We included 6 studies and found that pediatric patients with abnormal PET findings were about 17 times more likely to achieve definite diagnoses than those with normal PET findings (odds ratio [OR]: 16.75, 95% confidence interval [CI] 8.0-35, P < 0.00001). Sensitivity analyses using a fixed-effect model (OR 16.91, 95% CI 8.1-35, P < 0.0001) or removing one study at a time (OR 12-20, 95% CI lower bound 3.8-8.6, 95% CI upper bound 33-45, P < 0.0001) did not significantly alter the results. Sample size (interaction P = 0.75), imaging modality (interaction P = 0.29), length of follow-up (interaction P = 0.37), fever of unknown origin subclasses (interaction P = 0.89) and geographical areas (interaction P = 0.74) of studies showed no statistically significant influence on the results. CONCLUSION: 18F-FDG PET is a promising approach in the diagnostic work-up of pediatric fever of unknown origin. Further studies are warranted to support routine use in clinical care.

Optimal use of [18F]FDG-PET/CT in patients with fever or inflammation of unknown origin.

BACKGROUND: [18F]FDG-PET/CT is one of the most important diagnostic techniques in the work-up of patients with fever of unknown origin (FUO)/inflammation of unknown origin (IUO). Little is known on how to optimize the diagnostic value of [18F]FDG-PET/CT in patients with FUO/IUO. METHODS: Retrospective study in all patients who underwent [18F]FDG-PET/CT during the work-up of FUO/IUO in a tertiary expert center between 2005 and 2014. Data were extracted from medical records. RESULTS: One hundred and four patients were identified, of whom 68 had a final diagnosis (65.4%). Mainly infections (30.8%) and non-infectious inflammatory diseases (30.8%). [18F]FDG-PET/CT contributed to the final diagnosis in 47 of the 68 patients (69.1%). In 21 patients [18F]FDG-PET/CT did not help making a diagnosis. In ten of these patients [18F]FDG-PET/CT was performed while body temperature, CRP and ESR were normal or unknown. Sixteen of 104 patients underwent repeated [18F]FDG-PET/CT. The second scan contributed to the final diagnosis in five of these patients. In two of these patients, the first scan retrospectively was truly non-contributory. In both patients the first [18F]FDG-PET/CT was made while CRP/ESR was low and fever was not present or not measured. A third or fourth scan never contributed to the final diagnosis when the second one did not. CONCLUSIONS: [18F]FDG-PET/CT contributed to the final diagnosis in 45.2% of patients, but never contributed when both inflammatory parameters and body temperature were normal. Repeating [18F]FDG-PET/CT should only be done in patients with a non-contributory [18F]FDG-PET/CT when new symptoms or signs appear, or when the first scan was made in absence of fever or elevated inflammatory parameters.

Low threshold for intracranial imaging in fever of unknown origin associated with cyanotic heart disease in the pediatric population.

Intracranial abscess in the pediatric population is an overall rare occurrence-4 in a million. The most common predisposing factor is underlying cyanotic congenital heart disease (CCHD), which is associated with ~ 30% of all cases. We present an unusual case of cerebral abscess in a 17-month-old female with partially treated Tetralogy of Fallot and fever of unknown origin without associated neurologic symptoms. We propose a low threshold for intracranial imaging as part of the fever of unknown origin work-up in children with underlying cyanotic congenital heart disease.

Vascular Behcet's Disease Preceded by Fever of Unknown Origin: Usefulness of Ultrasonography for the Detection of Large-Vessel Vasculitis.

Behcet's disease is a systemic vasculitis characterized by oral and genital ulcers, erythema nodosum, and ocular involvement. Fever of unknown origin is a relatively rare event in Behcet's disease. We present the case of a 17-year-old male patient who suffered from prolonged fever for two months. The patient tested positive for HLA-B52 and levels of acute phase reactants were elevated. He complained of sore throat and neck pain that were evaluated by cervical ultrasonography, which revealed thickening of the carotid arterial wall and narrowing of the vessel lumen. The patient was diagnosed with vascular Behcet's disease and treated with glucocorticoid, which improved the clinical symptoms and thickening of the carotid arterial wall as detected by color duplex ultrasonography. Since vascular Behcet's disease may lead to morbidity and mortality, we suggest the early use of ultrasonography to help detect medium/large-vessel vasculitis. Prolonged fever in patients with Behcet's disease should be promptly evaluated for vascular involvement.

Predictors of Diagnostic Contributions and Spontaneous Remission of Symptoms Associated with Positron Emission Tomography with Fluorine-18-Fluorodeoxy Glucose Combined with Computed Tomography in Classic Fever or Inflammation of Unknown Origin: a Retrospective Study.

BACKGROUND: In patients with fever or inflammation of unknown origin (fever of unknown origin [FUO] or inflammation of unknown origin [IUO], respectively), expert consensus recommends the use of positron emission tomography with fluorine-18-fluorodeoxy glucose combined with computed tomography (FDG-PET/CT) when standard work-up fails to identify diagnostic clues. However, the clinical variables associated with successful localization of the cause by FDG-PET/CT remain uncertain. Moreover, the long-term outcomes of patients with unexplained FUO or IUO after negative FDG-PET/CT results are unknown. Therefore, we assessed predictors of successful diagnosis of FUO or IUO caused by FDG-PET/CT and associations of spontaneous remission of symptoms with FDG-PET/CT results. METHODS: All patients with FUO or IUO, who underwent FDG-PET/CT from 2013 to 2019 because diagnostic work-up failed to identify a cause, were retrospectively included. We calculated the diagnostic yield and performed multivariable logistic regression to assess characteristics previously proposed to be associated with successful localization of FUO or IUO causes. We also assessed whether the FDG-PET/CT results were associated with spontaneous remissions. RESULTS: In total, 50 patients with diagnostically challenging FUO or IUO (35 with FUO and 15 with IUO) were assessed. Other than one case of infection, all the identified causes were either malignancy or non-infectious inflammatory diseases (each with 18 patients), and FDG-PET/CT correctly localized the cause in 29 patients (diagnostic yield = 58%). None of the proposed variables was associated with successful localization. All 13 patients with sustained unexplained cause remained alive (median follow-up, 190 days). Spontaneous remission was observed in 4 of 5 patients with a negative FDG-PET/CT, and 1 of 8 with a positive result (P = 0.018). CONCLUSION: In the current cohort, the proposed variables were not predictive for successful localization by FDG-PET/CT. A negative FDG-PET/CT scan may be prognostic for spontaneous remission in patients with sustained FUO or IUO.

Role of FDG-PET/CT in children with fever of unknown origin.

PURPOSE: To determine the role of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET)/computed tomography (CT) in children with fever of unknown origin (FUO). METHODS: This retrospective single-center study included 110 children (0-18 years) with FUO who underwent FDG-PET/CT between 2010 and 2019. The diagnostic value of FDG-PET/CT for identifying cause of fever was calculated, treatment modifications after FDG-PET/CT were assessed, and logistic regression analyses were performed to identify clinical and biochemical factors associated with FDG-PET/CT outcome. RESULTS: In 53 out of 110 patients (48%), FDG-PET/CT identified a (true positive) cause of fever. Endocarditis (11%), systemic juvenile idiopathic arthritis (5%), and inflammatory bowel disorder (5%) were the most common causes of FUO. In 42 patients (38%), no cause of fever was found on FDG-PET/CT. In 58 out of 110 patients (53%), treatment modifications were made after FDG-PET/CT. FDG-PET/CT achieved a sensitivity of 85.5%, specificity of 79.2%, positive predictive value of 84.1%, and negative predictive value of 80.9%. On multivariate logistic regression, C-reactive protein was positively associated with finding a true positive focus of fever on FDG-PET/CT (OR = 1.01 (95% CI 1.00-1.02) per mg/L increase in CRP), while leukocyte count was negatively associated with finding a true positive focus of fever (OR = 0.91 (95% CI 0.85-0.97) per 109 leukocytes/L increase). CONCLUSION: FDG-PET/CT is a valuable diagnostic tool in the evaluation of children with FUO, since it may detect a true underlying cause in almost half (48%) of all cases where none was found otherwise. It allows full-body evaluation in patients without disease-specific symptoms on one examination. CRP and leukocyte count were significantly associated with FDG-PET/CT results, which may contribute to a priori assessment on the outcome of FDG-PET/CT. Future research could be aimed at evaluating more patient-specific factors to prospectively estimate the added value of FDG-PET/CT in children with FUO.

Findings in whole body MRI and conventional imaging in patients with fever of unknown origin-a retrospective study.

BACKGROUND: To analyse the influence of whole body (wb)-MRI on patient management compared to routine diagnostic tests in patients with fever of unknown origin (FUO). METHODS: Twenty-four patients with FUO, defined as illness of more than three weeks with fever greater than 38.3 °C, underwent wb-MRI at a 1.5 T MR-system. The MR-protocol consisted of the following sequences: axial T1 VIBE, coronal T2-TIRM and a coronal echoplanar diffusion weighted sequence (overall acquisition time 29:39 min:s). Furthermore, laboratory findings, chest-x-ray, abdominal ultrasound, CT-scans and/or PET-CT scans were evaluated and compared to the wb-MRI findings in regard to treatment changes. RESULTS: Wb-MRI yielded a correct diagnosis in 70% of the patients. In 46% the inflammatory focus was exclusively detected by wb-MRI. Focus detection by wb-MRI led to a subsequent change of the clinical management in 92% of the patients. In 6 patients both a wb-MRI and a PET-CT were performed yielding the correct diagnosis in the same 4 of 6 patients for both imaging modalities. CONCLUSIONS: Wb-MRI appears to be of value in the evaluation of FUO patients, allowing for optimized treatment by increasing diagnostic certainty. Due to its lack of nephrotoxicity and ionizing radiation it may be preferred over standard imaging techniques and PET-CT in the future. However, given the low number of patients in our trial, further prospective studies have to be performed to confirm our results.

18F-FDGPET/CT in fever of unknown origin and inflammation of unknown origin: a Chinese multi-center study.

PURPOSE: To evaluate the clinical value of 18F-FDG-PET/CT for the diagnosis of fever of unknown origin (FUO) and inflammation of unknown origin (IUO) in Chinese population, as well as the characteristics of PET/CT in different category of etiological disease. METHODS: A total of 376 consecutive patients with FUO/IUO who underwent FDG-PET/CT at 12 hospitals were retrospectively studied. FDG uptake was quantitatively and visually evaluated, by using SUVmax and a 4-grade scale respectively. A questionnaire survey to the clinicians was used to evaluate the significance of PET/CT in diagnosing of FUO/IUO. Data analysis included the etiological distribution in the study population, image characteristics in different category of diseases, and clinical significance of PET/CT. RESULTS: In 376 studied patients, the infectious diseases accounted for 33.0% of patients, rheumatologic diseases for 32.4%, malignancies for 19.1%, miscellaneous causes for 6.6%, and cause unknown for 8.8%. However, the etiological distribution among hospitals was varied. In addition, the etiological disease composition ratio has changed over time in China. On PET/CT examinations, 358 (95.2%) of the patients had a positive finding. Within them, local high uptake lesion was found in 219 cases, and nonspecific abnormal uptake (NAU) was found in 187 cases. FDG uptake in malignant diseases was significantly higher than in other category diseases both on SUVmax and visual scores (t-value range from 4.098 to 5.612, all P value < 0.001). Based on a clinical questionnaire survey, PET/CT provided additional diagnostic information for 77.4% of patients, and 89.6% of patients benefited from PET/CT examination. CONCLUSIONS: FDG PET/CT is a valuable tool for clinical diagnosis of FUO/IUO, and it is of great significance in further investigating the usefulness of PET/CT in non-neoplastic diseases.

Comparison between gallium-68 citrate positron emission tomography-computed tomography and gallium-67 citrate scintigraphy for infection imaging.

BACKGROUND: Preliminary studies have reported promising results for the utility of gallium-68 (Ga-68) citrate positron emission tomography-computed tomography (PET-CT) for infection imaging. This technique offers reduced radiation dose to patients, shorter time between injection and imaging and reduced time for image acquisition compared to the 'gold standard' nuclear imaging technique: gallium-67 (Ga-67) citrate scintigraphy. AIMS: To compare the two imaging modalities to ascertain whether Ga-68 citrate PET-CT is of equivalent diagnostic efficacy for bone and joint infection or pyrexia of unknown origin (PUO) and to assess image quality and reporter confidence. METHODS: Patients with PUO and suspected bone or joint infection underwent Ga-67 citrate scintigraphy and Ga-68 citrate PET-CT. Participants were followed up for 3 months to record subsequent treatment, investigations and outcome. RESULTS: 60 patients were recruited to this multicentre prospective study: 32 for bone and joint infection, 28 for PUO. The results show a sensitivity of 81% for Ga-67 citrate scintigraphy and 69% for Ga-68 citrate PET-CT, a specificity of 79% for Ga-67 citrate and 67% for Ga-68 citrate and were concordant for 76% of the participants. The reporting physician confidence was significantly lower for Ga-68 citrate (P < 0.05), frequently due to prominent physiologic blood pool activity adjacent to the site of infection. CONCLUSION: The sensitivity and specificity of Ga-68 citrate PET-CT were found to be consistently lower than Ga-67 citrate scintigraphy. Additionally, due to the insufficient level of confidence of the reporting physicians for the Ga-68 citrate PET-CT, this modality could not currently be recommended to replace Ga-67 citrate scintigraphy for routine clinical use.

Role of bone marrow biopsy for fever of unknown origin in the contemporary Australian context.

BACKGROUND: Bone marrow biopsy (BMB) is an accepted investigation in fever of unknown origin (FUO) to uncover haematological malignancies, such as lymphoma, and sometimes infections. With the advance in imaging modalities, such as 18-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) to identify the focus of lymphoma, BMB may not contribute to the diagnosis when there are no other clinical features to suggest an underlying haematological disease. AIM: To investigate the utility of BMB in determining the cause of FUO, when there are no other indications for BMB. METHODS: Medical records of adult patients who had BMB performed for FUO or febrile illness from 1 January 2005 to 31 December 2014 in four metropolitan tertiary hospitals in Melbourne, Australia were reviewed. Patients with other concurrent indications for BMB, known human immunodeficiency virus infection and previously diagnosed connective tissue diseases were excluded. RESULTS: Seventy-three patients were included in the study. Fifty-one patients had a final diagnosis for fever (systemic inflammatory diseases, infective, malignancy or other) while 22 patients had no diagnoses. In only 10 patients (13.7%) did BMB contribute to the diagnosis, finding either malignancy or granulomata. However, all these diagnoses could have been made without BMB. Two patients with diffuse large B-cell lymphoma had normal BMB. FDG-PET was helpful in making a diagnosis in eight (25%) out of 32 patients. CONCLUSION: Performing BMB in patients with FUO and no other haematological abnormalities is of very limited value, and other investigations, such as FDG-PET, may be more likely to help establish a definitive diagnosis.

Contribution of 18F-FDG PET/CT in a case-mix of fever of unknown origin and inflammation of unknown origin: a meta-analysis.

BACKGROUND: Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are challenging medical problems. Previous studies have shown that 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) plays an important role in the diagnosis of FUO, but few studies have explored this diagnostic technique in relation to IUO. PURPOSE: To systematically review and perform a meta-analysis of published data on the diagnostic performance of PET/CT in the diagnosis of FUO and IUO. MATERIAL AND METHODS: A comprehensive literature search was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines published in March 2018. Meta-analysis of diagnostic performance was performed using STATA 12.0 software. Subgroup analysis was performed by stratification based on study design, number of patients, geographic area, and final diagnosis based on 18F-FDG PET/CT. Meta-regression analyses were performed to recognize heterogeneity. RESULTS: Our meta-analysis included 23 studies, comprising a total sample size of 1927 patients. The pooled diagnosis performance was calculated with a per-patient-based analysis: sensitivity = 0.84 (95% confidence interval [CI] = 0.79-0.89), specificity = 0.63 (95% CI = 0.49-0.75), positive likelihood ratio = 2.3 (95% CI = 1.5-3.4), negative likelihood ratio = 0.25 (95% CI = 0.16-0.38), diagnostic odds ratio = 9 (95% CI = 4.0-20), and AUC = 0.84 (95% CI = 0.81-0.87). CONCLUSION: In patients with non-specific symptoms and signs, 18F-FDG PET/CT is very helpful for recognizing and excluding diseases, directing further diagnostic decisions, and avoiding unnecessary invasive examinations. We recommend that 18F-FDG PET/CT should be considered among the first-line diagnostic tools for patients with FUO and IUO.

Diagnostic utility of 18F-FDG PET/CT in fever of unknown origin among patients with end-stage renal disease treated with renal replacement therapy.

OBJECTIVE: To evaluate the role of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in identifying the cause of fever of unknown origin (FUO) in patients on renal replacement therapy (RRT) for end-stage renal disease (ESRD). SUBJECTS AND METHODS: We retrospectively reviewed the 18F-FDG PET/CT scans of 46 patients with a mean age of 39.28±12.50 years on RRT for ESRD. All patients with abnormal scans had histopathologic examination and microbial cultures of tissue samples from areas with increased standardized uptake value maximum (SUVmax) suggesting the cause of FUO in the 18F-FDG PET/CT scan. Fluorine-18-FDG PET/CT was considered helpful if it led to the diagnosis of the cause of FUO after histopathologic and microbiologic examinations. RESULTS: Fluorine-18-FDG PET/CT was helpful in identifying the cause of FUO in 22/46 patients (47.83%). Infection was the cause of fever in all these 22 patients. C-reactive protein (CRP) (P=0.003) and procalcitonin levels (P=0.021) were higher in patients with helpful 18F-FDG PET/CT. No significant difference was found in blood sugar levels and leucocytes counts between patients with helpful 18F-FDG PET/CT outcome and those without. By multiple regression analysis, the odds of a helpful 18F-FDG PET/CT increased with every unit increase in CRP level (OR: 1.009; 95% CI: 1.003-1.016; P=0.005). CONCLUSION: About half of the 18F-FDG-PET/CT scans (22/46) identified the cause of FUO in patients on RRT for ESRD. The clinical utility of 18F-FDG PET/CT in this group of patients is comparable to its average performance in the unselected patients' population evaluated for FUO. A higher CRP level was predictive of a positive 18F-FDG PET/CT outcome.