Fever of Unknown Origin: the Value of FDG-PET/CT.

Fever of unknown origin (FUO) is commonly defined as fever higher than 38.3°C on several occasions during at least 3 weeks with uncertain diagnosis after a number of obligatory investigations. The differential diagnosis of FUO can be subdivided in four categories: infections, malignancies, noninfectious inflammatory diseases, and miscellaneous causes. In most cases of FUO, there is an uncommon presentation of a common disease. FDG-PET/CT is a sensitive diagnostic technique for the evaluation of FUO by facilitating anatomical localization of focally increased FDG uptake, thereby guiding further diagnostic tests to achieve a final diagnosis. FDG-PET/CT should become a routine procedure in the workup of FUO when diagnostic clues are absent. FDG-PET/CT appears to be a cost-effective routine imaging technique in FUO by avoiding unnecessary investigations and reducing the duration of hospitalization.

Evaluation of Spleen Glucose Metabolism Using 18F-FDG PET/CT in Patients with Febrile Autoimmune Disease.

The purpose of this study was to evaluate the clinical significance of 18F-FDG uptake by the spleen in patients with autoimmune disease. Methods: We retrospectively reviewed Severance Hospital's electronic medical records of patients hospitalized for the evaluation of fever who underwent 18F-FDG PET/CT. We found 91 patients with autoimmune diseases and 101 patients with localized infection. 18F-FDG uptake was assessed by measuring SUV in the spleen and liver. The spleen-to-liver ratio of the SUVmean (SLRmean) was calculated. Clinical and laboratory parameters were collected and evaluated for association with SLRmean In-hospital mortality was defined as all-cause mortality during hospital admission for fever. Results: SLRmean was significantly higher in autoimmune disease than in localized infectious disease (1.28 ± 0.43 vs. 0.91 ± 0.21, P < 0.001). In autoimmune disease, SLRmean was correlated with monocytes, aspartate aminotransferase, alanine aminotransferase, albumin, and ferritin. Analysis of receiver-operating-characteristic curves revealed that in comparison with laboratory parameters, SLRmean had the highest performance in differentiating autoimmune from localized infectious disease. Multivariate logistic regression analysis demonstrated that high SLRmean and low platelets were significantly associated with in-hospital mortality in febrile autoimmune disease. Conclusion: These findings suggest that spleen glucose metabolism is increased in febrile autoimmune disease. Spleen 18F-FDG uptake may provide information useful in differentiating febrile autoimmune disease from localized infectious disease and predicting clinical outcomes in febrile autoimmune disease.

PET Index of Bone Glucose Metabolism (PIBGM) Classification of PET/CT Data for Fever of Unknown Origin Diagnosis.

OBJECTIVES: Fever of unknown origin (FUO) remains a challenge in clinical practice. Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is helpful in diagnosing the etiology of FUO. This paper aims to develop a completely automatic classification method based on PET/CT data for the computer-assisted diagnosis of FUO. METHODS: We retrospectively analyzed the FDG PET/CT scan of 175 FUO patients, 79 males and 96 females. The final diagnosis of all FUO patients was achieved through pathology or clinical evaluation, including 108 normal patients and 67 FUO patients. CT anatomic information was used to acquire bone functional information from PET images. The skeletal system of FUO patients was classified by analyzing the standardized uptake value (SUV) and the PET index of bone glucose metabolism (PIBGM). The SUV distributions in the bone marrow and the bone cortex were also studied in detail. RESULTS: The SUV and PIBGM of the bone marrow only slightly differed between the FUO patients and normal people, whereas the SUV of whole bone structures and the PIBGM of the bone cortex significantly differed between the normal people and FUO patients. The method detected 43 patients from 67 FUO patients, with sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 64.18%, 95%, 93.48%, 72.73%, and 83.33%, respectively. CONCLUSION: The experimental results demonstrate that the study can achieve automatic classification of FUO patients by the proposed novel biomarker of PIBGM, which has the potential to be utilized in clinical practice.

The predictive value of C-reactive protein and erythrocyte sedimentation rate for 18F-FDG PET/CT outcome in patients with fever and inflammation of unknown origin.

OBJECTIVES: The objective of this study was to determine the predictive value of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) to a positive fluorine-18 fluorodeoxyglucose ((18)F-FDG) PET/computed tomography (CT) result in patients with inflammation of unknown origin and fever of unknown origin. PATIENTS AND METHODS: Individual data of 498 patients were retrieved from three retrospective studies. Receiver operating characteristic derived areas under the curve were used to assess (18)F-FDG PET/CT versus age, CRP, and ESR. The discriminative value of age, CRP, and ESR related to (18)F-FDG PET/CT was examined using the net reclassification improvement (NRI). RESULTS: A diagnosis was established in 331 patients; (18)F-FDG PET/CT had a diagnostic accuracy of 89%. (18)F-FDG PET/CT had the highest area under the curve (0.89, P<0.001). The addition of (18)F-FDG PET/CT to a diagnosis prediction model including age, CRP, and ESR resulted in an NRI of 42% (P<0.001). In the same model with CRP values below 20 mg/l or ESR values below 20 mm/h, the NRI was 64% (P<0.001) and 29% (P=0.059), respectively. In 30 of 91 patients with CRP less than 10 mg/l, a diagnosis could be established; (18)F-FDG PET/CT was 100% true negative only in patients with CRP levels less than 5 mg/l. CONCLUSION: In patients with fever of unknown origin or inflammation of unknown origin, compared with elevated ESR levels, elevated CRP levels more often indicate a true positive (18)F-FDG PET/CT outcome.In addition, (18)F-FDG PET/CT, compared with CRP and ESR, shows the highest discrimination of patients with possible disabling disease.

Accuracy of a sequential approach to identify young febrile infants at low risk for invasive bacterial infection.

INTRODUCTION: Much effort has been put in the past years to create and assess accurate tools for the management of febrile infants. However, no optimal strategy has been so far identified. A sequential approach evaluating, first, the appearance of the infant, second, the age and result of the urinanalysis and, finally, the results of the blood biomarkers, including procalcitonin, may better identify low risk febrile infants suitable for outpatient management. OBJECTIVE: To assess the value of a sequential approach ('step by step') to febrile young infants in order to identify patients at a low risk for invasive bacterial infections (IBI) who are suitable for outpatient management and compare it with other previously described strategies such as the Rochester criteria and the Lab-score. METHODS: A retrospective comparison of three different approaches (step by step, Lab-score and Rochester criteria) was carried out in 1123 febrile infants less than 3 months of age attended in seven European paediatric emergency departments. IBI was defined as isolation of a bacterial pathogen from the blood or cerebrospinal fluid. RESULTS: Of the 1123 infants (IBI 48; 4.2%), 488 (43.4%) were classified as low-risk criteria according to the step by step approach (vs 693 (61.7%) with the Lab-score and 458 (40.7%) with the Rochester criteria). The prevalence of IBI in the low-risk criteria patients was 0.2% (95% CI 0% to 0.6%) using the step by step approach; 0.7% (95% CI 0.1% to 1.3%) using the Lab-score; and 1.1% (95% CI 0.1% to 2%) using the Rochester criteria. Using the step by step approach, one patient with IBI was not correctly classified (2.0%, 95% CI 0% to 6.12%) versus five using the Lab-score or Rochester criteria (10.4%, 95% CI 1.76% to 19.04%). CONCLUSIONS: A sequential approach to young febrile infants based on clinical and laboratory parameters, including procalcitonin, identifies better patients more suitable for outpatient management.

Hemophagocytic syndrome in children with acute monoblastic leukemia-another cause of fever of unknown origin.

PURPOSE: Intensification of antileukemic treatment and progress in supportive management have improved the survival rates of children with acute myeloid leukemia (AML). However, morbidity and early mortality in these patients are still very high, especially in children with acute monoblastic leukemia (AML FAB M5). Inflammatory syndromes complicating the management of these children after application of cytosine arabinoside and due to hyperleukocytosis at initial presentation have been reported. Hemophagocytic lymphohistiocytosis (HLH) has been described as a serious and life-threatening acute complication during treatment of different oncologic entities; however, data on HLH in children with AML FAB M5 are extremely rare. METHODS: A retrospective study of all children with AML FAB M5 treated at our institution between 1993 and 2013 was performed to describe the clinical characteristics of patients who developed an inflammatory syndrome with HLH during oncologic treatment. RESULTS: Three of 10 children developed an inflammatory syndrome with fever, elevation of C-reactive protein, hyperferritinemia, elevation of soluble interleukin-2, and hemophagocytosis during prolonged aplasia following the first cycle of chemotherapy not responding to broad-spectrum antibiotics. No infectious agents could be identified; the initial symptoms occurred 17, 18, and 28 days after diagnosis of AML, respectively. The children immediately responded to dexamethasone; however, the same syndrome was observed again after the second cycle of chemotherapy and, in one patient, also after the third cycle. CONCLUSIONS: Treating physicians should be aware of an inflammatory syndrome resembling HLH in children with monoblastic leukemia since this problem might extremely complicate management and supportive care of these children. The co-incidence of monoblastic leukemia with HLH might be explained by cytokines released from the monoblastic leukemic cells themselves.

A comprehensive analysis of 174 febrile patients admitted to Okayama University Hospital.

Primary care physicians often encounter patients with fever of unknown origin and without apparent causes. Recent advances in laboratory medicine have facilitated diagnostic procedures;however, it is still difficult to determine the critical febrile factor at an early stage. We reviewed the medical records of 174 patients who were admitted due to a chief complaint of fever (>37.5℃) to our hospital during the period from 2004 to 2010. The patients were categorized into patients with infection, inflammation, neoplasm and drug-induced fever. Based on the analysis done by category, it was revealed that the patient's age, body temperature and duration of fever were closely related to the final diagnosis. Serum CRP levels were significantly low in the nonbacterial infection group, while serum levels of sIL-2R were high in neoplasm and drug-induced cases. CRP level on admission was weakly but significantly correlated with body temperature, while duration of fever was inversely related to body temperature. The effectiveness of PET-CT and tissue biopsy for diagnosis was considerably high, particularly in the categories of neoplasm and nonspecific inflammation, respectively, though the effectiveness of bacterial culture was low. Thus, a careful review of physical and laboratory information including body temperature, CRP level, duration of fever, gender difference and history of medication is indispensable for diagnosis. Stepwise categorization and disease classification by comprehensive and systemic checkup are very helpful for determining the causes of fever.

Clinical features of 66 lymphoma patients presenting with a fever of unknown origin.

OBJECTIVE: To investigate the clinical characteristics, diagnostic approaches, short-term efficacy of treatment and prognosis of lymphoma patients presenting with a fever of unknown origin (FUO). METHODS: We reviewed the records of 132 patients finally diagnosed with lymphoma in Huashan Hospital, half of whom initially presented with a FUO. The other 66 lymphoma patients without a history of FUO were diagnosed within a month when several patients in the FUO group were also diagnosed. RESULTS: The patients presenting with a FUO were predominantly young men (71.21%, p=0.35) characterized by a temperature ≥ 39°C (55/66, 83.33%). Compared with the non-FUO group, patients in the FUO group more often had pancytopenia and hypohepatia, 61.54% with hypoalbuminemia (p<0.0001), 15.50% with significantly elevated lactate dehydrogenase (LDH) (p<0.0001), 92.45% with elevated serum ß(2) microglobulin (p=0.017), 93.48% with elevated urine ß(2) microglobulin (p=0.002) and 30.77% with elevated alkaline phosphatase (p=0.001). Ninety-four percent of the FUO patients had aggressive lymphomas (p=0.012), with a poor performance status (96.97%, p=0.003), stage III/IV disease (96.97%, p<0.0001), night sweats (21.21%, p=0.026), unexplained weight loss (46.97%, p=0.002) and more than one extranodal site involved (65.15%, p=0.002). The patients in the FUO group also showed poor prognoses, and most of them were in the high-intermediate or high risk classification of the disease (96.61%, p<0.0001), with a low complete remission (CR) rate (61.11% vs. 93.75%, p=0.043). Twenty-one (15.91%) of all the patients were diagnosed based on the finding of lesion sites by Positron Emission Tomography/Computed Tomography (PET/CT) scanning, which had not been detected by conventional scans. CONCLUSION: Lymphoma presenting as FUO has a rapid progression and poor prognosis, and is difficult to diagnose. PET/CT scans can provide complementary information for an etiological diagnosis of a FUO and biopsy examinations are significant to establish an early diagnosis for patients presenting with a FUO.

Low prevalence of invasive bacterial infection in febrile infants under 3 months of age with enterovirus infection.

Infants under 3 months of age with fever without source (FWS) generally undergo a full, invasive septic evaluation to exclude invasive bacterial infection (IBI). Enterovirus (EV) infections are mostly banal and self-limiting and show a high prevalence rate at this age. We aimed to investigate the prevalence of IBI in EV-infected and uninfected infants under 3 months of age with FWS. This was a prospective observational cohort study of infants aged <90 days who were admitted because of FWS. As per protocol, blood and urine analysis and culture were obtained in all cases, and RNA EV from blood and/or cerebrospinal fluid samples was determined by real-time PCR. Three hundred and eighty-one previously healthy infants with FWS were included. EV infection was diagnosed in 64 children (16.8%; 95% confidence interval, 13.2-20.9%) and showed an uneventful evolution in all cases. Laboratory markers of infection were consistently lower in EV-infected patients; only one case of IBI (1.6%) was observed in an EV-infected patient as compared with 25.2% in EV-negative infants (p <0.001). Intravenous antibiotic use and length of stay were no different in EV-infected and uninfected patients. In our study, febrile infants (<90 days) diagnosed with EV infection showed a low risk of IBI when compared with uninfected patients. The systematic investigation of EV infection in young infants with FWS may allow a more conservative approach to the management of these patients. Further studies on this diagnostic approach are needed.

FDG-PET in patients with fever of unknown origin: the importance of diagnosing large vessel vasculitis.

This review analyzes the impact of 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET) in the diagnostic work-up of classic fever of unknown origin (FUO) according to the criteria first proposed by Petersorf in 1961 and later modified by Durack et al. in 1991. Algorithms currently used in this diagnostic process are not strictly evidence based up to now. FDG accumulates in malignant tissues, but also in inflammatory cells by the overexpression of facultative glucose transporter-isotypes (mainly GLUT-1 and GLUT-3) and by an overproduction of glycolytic enzymes. Therefore, this technique covers a broad spectrum of possible etiologies for FUO. Once imaged, these lesions can be further investigated by other (e.g. invasive) and more specific methods. Until now, four prospective studies using FDG-PET in patients with classic FUO, encompassing 167 patients in total are published. Three retrospective studies with 125 patients are also available. These studies are discussed and weighted according to the control of selection-bias that was performed. An interstudy-bias may also be present resulting from a considerable variability in causes of FUO. A low number of diagnostic scans in a study may sometimes be related to a high rate of fevers caused by miscellaneous disorders or to a high rate of undiagnosed patients. In these disease categories, focal pathologies that can be imaged with FDG-PET, are rare. A high number of diagnostic scans is always related to a high prevalence of patients with medium- and large-vessel vasculitis. Available data indicate that FDG-PET has the potential to play an important role as a second line procedure in the management of about 1/3 of patients with classic FUO. It is expected that hybrid imaging (PET/computed tomography [CT]; PET/magnetic resonance imaging [MRI]) will improve the diagnostic impact of FDG-PET further, but prospective data about the value of this methods are currently not available. The question as to how these new techniques can be implemented into an evidence based diagnostic algorithm, can only be resolved within a multidisciplinary setting, avoiding both selection- and interstudy-bias whenever possible.

Nuclear medicine and infection detection: the relative effectiveness of imaging with 111In-oxine-, 99mTc-HMPAO-, and 99mTc-stannous fluoride colloid-labeled leukocytes and with 67Ga-citrate.

With a current annual mortality rate of around 35% worldwide, infection remains a significant concern, and the diagnosis and localization of infectious foci is an important health issue. As an established infection-imaging modality, nuclear medicine plays a vital health-care role in the diagnosis and subsequent effective treatment of this condition. Despite the development of several newer radiopharmaceuticals, (67)Ga and leukocyte imaging procedures have maintained their established place for infection. Several techniques in nuclear medicine significantly aid infection diagnosis, including imaging with (111)In-oxine-, (99m)Tc-hexamethylpropyleneamine oxime-, and (99m)Tc-stannous fluoride colloid-labeled leukocytes and with (67)Ga-citrate. Each radiopharmaceutical has specific advantages and disadvantages that make it suitable to diagnose different infectious processes (e.g., soft-tissue sepsis, inflammatory bowel disease, osteomyelitis, occult fever, fever of unknown origin, and infections commonly found in immunocompromised patients). After finishing this article, the reader should be able to identify the properties of an ideal radiopharmaceutical for infection imaging, list a range of available infection-imaging radiopharmaceuticals, compare the relative results of a range of radiopharmaceuticals used internationally to detect infection in the body, understand several common infectious processes that can be diagnosed using nuclear medicine techniques, and select an appropriate radiopharmaceutical to image a range of infectious processes.

18-fluorodeoxyglucose positron emission tomographic imaging in the detection and monitoring of infection and inflammation.

During the past decade, 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) has rapidly evolved from a pure research modality to a clinical necessity. FDG-PET was introduced to determine the state of brain function in physiologic and pathologic states. Its use as a powerful tool to diagnose, stage, and monitor patients with a variety of malignancies has been truly revolutionary. However, FDG is a nonspecific tracer and it has been found to accumulate at sites of infection and inflammation. It is becoming evident that PET imaging will play a major role in the treatement of patients with suspected infection and inflammation. PET has been shown to be particularly valuable in the evaluation of chronic osteomyelitis, infected prostheses, sarcoidosis, fever of unknown origin, and acquired immunodeficiency syndrome. Because of its ability to quantitate the rate of FDG uptake, PET may prove to be a powerful modality for the monitoring of disease activity and response to therapy. Novel PET tracers are being tested for imaging infection and inflammation that may further enhance the role of this technique in the appropriate clinical setting. PET imaging to detect and characterize infection and inflammation may become a major clinical indication in the day-to-day practice of medicine.

Defective monocyte oxidative metabolism in a child with Smith-Lemli-Opitz syndrome.

We present a patient with Smith-Lemli-Opitz syndrome with immunodeficiency. The patient suffered numerous infectious episodes, atopic dermatitis and wheezing. Immunological investigations demonstrated severely reduced oxidative burst-responsiveness of the blood monocytes, whereas chemotaxis, phagocytosis and interleukin-1 production were normal. Tests of neutrophils and lymphocytes were normal excluding previously described immune deficiency disorders. The father proved to have diminished monocyte oxidative metabolism as well, whereas the mother had normal monocyte function. The genetic and immunological aspects are discussed in relation to the syndrome.

Liquor:serum quotients of IgG and albumin in patients with meningism, meningitis and multiple sclerosis.

Liquor:serum quotients of IgG and albumin in patients with meningism, meningitis and multiple sclerosis have been studied. Abnormal quotients indicative of disturbed blood-brain barrier function and/or intrathecal IgG synthesis were found in various proportions of all 3 groups of patients. In some patients with aseptic meningitis and meningism, the abnormal quotients were comparable with those found in patients with multiple sclerosis. The reason for this is unknown. An unspecific reaction to febrile illness may be involved. As a consequence, the findings of abnormal liquor:serum quotients of IgG and albumin should be evaluated with great caution in patients with recent or present febrile illness.