Classical Fever Of Unknown Origin Research Articles

Recurrent (or episodic) fever of unknown origin (FUO) as a variant subgroup of classical FUO: A French multicentre retrospective study of 170 patients

BackgroundRecurrent FUO (fever of unknown origin) is a rare subtype of FUO for which diagnostic procedures are ill-defined and outcome data are lacking. MethodsWe performed a retrospective multicentre study of patients with recurrent FUO between 1995 and 2018. By multivariate analysis, we identified epidemiological, clinical and prognostic variables independently associated with final diagnosis and mortality. ResultsOf 170 patients, 74 (44%) had a final diagnosis. Being ≥ 65 years of age (OR = 5.2; p < 0.001), contributory history (OR = 10.4; p < 0.001), and abnormal clinical examination (OR = 4.0; p = 0.015) independently increased the likelihood of reaching a diagnosis, whereas lymph node and/or spleen enlargement decreased it (OR = 0.2; p = 0.004). The overall prognosis was good; 58% of patients recovered (70% of those with a diagnosis). Twelve (7%) patients died; patients without a diagnosis had a fatality rate of 2%. Being ≥ 65 years of age (OR = 41.3; p < 0.001) and presence of skin signs (OR = 9.5; p = 0.005) significantly increased the risk of death. ConclusionThis study extends the known yield of recurrent FUO and highlights the importance of repeated complete clinical examinations to discover potential diagnostic clues during follow-up. Moreover, their overall prognosis is excellent.

The Contribution of 18F FDG PET-CT for the Investigation of Fever of Unknown Origin and Inflammation of Unknown Origin

BackgroundFever of unknown origin and inflammation of unknown origin are highly challenging diagnostic conditions. The current practice for evaluating patients is to conduct a positron emission tomography-computed tomography (PET-CT) scan as either a first- or a second-line modality. We aimed to assess the contributory effect of PET-CT to the diagnosis and compare it with the contributory effect of CT alone. MethodsWe performed a systematic review and meta-analysis. We included all cohorts that examined the contribution of PET-CT to the investigation of classical fever of unknown origin and inflammation of unknown origin. The primary outcome was the contribution of PET-CT to the final diagnosis. Secondary outcomes were sensitivity and specificity of PET-CT and CT scans, and contribution of a CT scan. We pooled the results of all studies and calculated the pooled contributory effect of PET-CT. ResultThirty-six studies (3516 patients) were included in the systematic review. The pooled contribution of PET-CT was 75.4%. The compiled sensitivity and specificity values for all studies were 85.9% and 59.5%, respectively. Five studies (405 patients) compared between the PET-CT component and the total body CT component. The pooled contribution of a CT scan was 68%. The summed sensitivity and specificity values of a CT scan for all studies were 63.1% and 84.4%, respectively. ConclusionsPET-CT has a contributory effect of 75% for the diagnosis of fever of unknown origin and inflammation of unknown origin. PET-CT had superior sensitivity and inferior specificity vs the CT scan.

Machine Learning to Predict Etiology for Infectious Diseases of Classic Fever of Unknown Origin in Adults

Machine Learning to Predict Etiology for Infectious Diseases of Classic Fever of Unknown Origin in Adults

Differential diagnosis of lymphoma with 18F-FDG PET/CT in patients with fever of unknown origin accompanied by lymphadenopathy

PurposeTo investigate the value of 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the differential diagnosis of lymphoma in patients with fever of unknown origin (FUO) accompanied by lymphadenopathy and to develop a simple scoring system to distinguish lymphoma from other etiologies.MethodsA prospective study was conducted on patients with classic FUO accompanied by lymphadenopathy. After standard diagnostic procedures, including PET/CT scan and lymph-node biopsy, 163 patients were enrolled and divided into lymphoma and benign groups according to the etiology. The diagnostic utility of PET/CT imaging was evaluated, and beneficial parameters that could improve diagnostic effectiveness were identified.ResultsThe sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PET/CT in diagnosing lymphoma in patients with FUO accompanied by lymphadenopathy were 81.0, 47.6, 59.3, and 72.7%, respectively. The lymphoma prediction model combining high SUVmax of the “hottest” lesion, high SUVmax of the retroperitoneal lymph nodes, old age, low platelet count, and low ESR had an area under the curve of 0.93 (0.89–0.97), a sensitivity of 84.8%, a specificity of 92.9%, a PPV of 91.8%, and an NPV of 86.7%. There was a lower probability of lymphoma for patients with a score < 4 points.ConclusionsPET/CT scans show moderate sensitivity and low specificity in diagnosing lymphoma in patients with FUO accompanied by lymphadenopathy. The scoring system based on PET/CT and clinical parameters performs well in differentiating lymphoma and benign causes and can be used as a reliable noninvasive tool.Registration numberThis study on FUO was registered on http://www.clinicaltrials.gov on January 14, 2014, with registration number NCT02035670.

Classical fever of unknown origin in 21 countries with different economic development: an international ID-IRI study.

Fever of unknown origin (FUO) is a serious challenge for physicians. The aim of the present study was to consider epidemiology and dynamics of FUO in countries with different economic development. The data of FUO patients hospitalized/followed between 1st July 2016 and 1st July 2021 were collected retrospectively and submitted from referral centers in 21 countries through ID-IRI clinical research platform. The countries were categorized into developing (low-income (LI) and lower middle-income (LMI) economies) and developed countries (upper middle-income (UMI) and high-income (HI) economies). This research included 788 patients. FUO diagnoses were as follows: infections (51.6%; n = 407), neoplasms (11.4%, n = 90), collagen vascular disorders (9.3%, n = 73), undiagnosed (20.1%, n = 158), miscellaneous diseases (7.7%, n = 60). The most common infections were tuberculosis (n = 45, 5.7%), brucellosis (n = 39, 4.9%), rickettsiosis (n = 23, 2.9%), HIV infection (n = 20, 2.5%), and typhoid fever (n = 13, 1.6%). Cardiovascular infections (n = 56, 7.1%) were the most common infectious syndromes. Only collagen vascular disorders were reported significantly more from developed countries (RR = 2.00, 95% CI: 1.19-3.38). FUO had similar characteristics in LI/LMI and UMI/HI countries including the portion of undiagnosed cases (OR, 95% CI; 0.87 (0.65-1.15)), death attributed to FUO (RR = 0.87, 95% CI: 0.65-1.15, p-value = 0.3355), and the mean duration until diagnosis (p = 0.9663). Various aspects of FUO cannot be determined by the economic development solely. Other development indices can be considered in future analyses. Physicians in different countries should be equally prepared for FUO patients.

Predictors for spontaneous resolution of classical FUO in patients undergoing PET-CT.

Spontaneous resolution is common in patients with classic fever of unknown origin (FUO). Identifying predictors of spontaneous resolution could reduce the usage of unnecessary, invasive tests or empirical therapy, and furthermore reduce patient anxiety. Identify predictors associated with spontaneous resolution of FUO. A single center, retrospective, cohort study. All hospitalized patients who underwent an [18F] FDG PET-CT scan for the investigation of classical FUO between 1/2012 and 1/2020 were included. We compared patients with spontaneous resolution of fever and clinical symptoms, to those who were diagnosed with a specific etiology of FUO (subdivided to infectious diseases, non-infectious inflammatory diseases (NIID), and malignancies). Epidemiologic characteristics as well as laboratory and PETCT study results were compared. Variables that were found to be associated with spontaneous resolution of FUO on univariate analysis (p < 0.1) were entered into a multivariable regression analysis. The results are reported as odds ratios (OR) and 95% confidence intervals (CI). A total of 303 patients were hospitalized for the investigation of classical FUO and underwent complete assessment. Fever resolved without a diagnosis in 84/303 patients (28%). Variables that were associated with spontaneous resolution of FUO on multivariable analysis included: no anemia, no hypoalbuminemia and no pathological FDG uptake on PET-CT. In 17.8% (15/84) of studies, PET-CT yielded false-positive results that led to additional unnecessary, invasive investigation. Patients without anemia or hypoalbuminemia, and those without uptake on PET-CT are more likely to have spontaneous resolution of classical FUO.

Prospective Study of the Usefulness of Liquid Biopsy in Patients with Unknown Fever Suspected of Malignant Lymphoma

Background: Malignant lymphoma, represented by intravascular large B-cell lymphoma (IVLBCL), is an important differential disease in classical fever of unknown origin (FUO). Bone marrow aspiration (BMA) and random skin biopsy (RSB) are useful in IVLBCL diagnosis, but their positivity rates are clinically insufficient and the procedures are invasive. The molecular genetic analysis of lymphomas using cell-free tumor DNA (cfDNA) in plasma (liquid biopsy) may be effective for IVLBCL (Shimada et al., Blood. 2021 Mar 18;137(11):1491). We conducted a multicenter prospective clinical trial to investigate the usefulness of liquid biopsy for early lymphoma diagnosis among patients with classical FUO. Methods: Patients with the following criteria were enrolled: (1) clinically suspected malignant lymphoma, (2) persistent fever for >3 weeks, refractory to antibiotics, (3) higher than standard lactate dehydrogenase, (4) unbiopsiable lesions, and (5) age ≥20 years. Liquid biopsies were performed as follows: (1) MYD88 L265P/CD79 Y196 mutation analysis using droplet digital PCR (ddPCR), (2) B-cell receptor (BCR)/T-cell receptor (TCR) reconstruction analysis using next generation sequencing (NGS), and (3) comprehensive genetic analysis using the hematopoietic oncogene panel (426 genes) and NGS. Pathological malignant lymphoma was diagnosed at each institution; later, a central diagnosis was made by two additional lymphoma pathology specialists. Results: Fifty patients were enrolled from 15 centers from October 2019 to September 2021; one was excluded. The median age was 73.5 (21-89) years; 28 patients (57.1%) were male. There were 29 cases (59%), 28 (57.1%), and one (2%) of hematologic malignancy, malignant lymphoma, and MDS/AML, respectively (Fig. 1A). Twenty (71%) malignant lymphomas were B-cell lymphomas (17 of which were IVLBCL [61%]), and 8 (29%) were mature T/NK-cell lymphomas. Nonhematologic diseases were present in 20 (41%) patients (7 collagen diseases [4 adult-onset Still's disease, 3 others], 2 solid tumors, 2 infections [1 syphilis, 1 tuberculosis], and 9 FUO). FUO pathological investigations were performed in 47 (97.9%) and 43 (87.6%) patients with BMA and RSB, respectively. IVLBCL had a 53% positivity rate for initial BMA (9/17) and RSB (8/15; Fig. 1B). Only 65% patients tested positive for either initial BMA or RSB and a majority (15/17) of them were diagnosed based on repeated evaluations during their lifetime. The BMA positive rate in patients with mature T/NK-cell lymphoma (8 cases) was high (75%). The mean cfDNA concentration was 215 (5.6-1320) ng/mL, with no significant difference between patients with lymphoma and those with other diseases (279 vs. 130 ng/mL, p=0.073). In ddPCR analysis, 85% of B-cell lymphoma cases (N=20) had either MYD88 or CD79B mutations; the mutation detection rate in IVLBCL (N=17) was 94% (Fig.1B, 2). All patients with non-B-cell lymphoma tested negative. The positive rate of patients with B-cell lymphoma in the NGS-based BCR reconstruction analysis was 90% and negative in two patients with IVLBCL. BCR reconstitution was also observed in two patients with T/NK-cell lymphoma. Comprehensive panel analysis demonstrated that 19/20 (95%) B-cell lymphoma cases showed MYD88 or CD79B mutations; all IVLBCL cases showed mutations. LymphGen algorithm analysis showed that 15, 1, and 1 IVLBCL cases were categorized as MCD (with MYD88 or CD79b mutations), composite (including MCD), and other, respectively (Fig. 2). In T/NK-cell lymphomas, TCR reconstitution was positive in 3/8 T/NK-cell lymphomas. Panel analysis could hardly predict T/NK-cell lymphoma. DdPCR results were returned to the physician within a median time of 14 days. Of the six patients who were not diagnosed with initial BMA and RSB, five were positive for the MYD88/CD79B mutation, according to the ddPCR results. Three of them were diagnosed through additional liquid biopsy testing. Two patients were diagnosed with IVLBCL based on central diagnosis after death. Conclusions: In the classical FUO cases with suspected malignant lymphoma, 57% and 35% had malignant lymphoma and IVLBCL, respectively. Compared to the classical diagnostic methods, liquid biopsy can be used to detect lymphoma-specific genetic mutations at an earlier stage, being clinically useful for the early diagnosis of difficult-to-diagnose malignant B-cell lymphomas. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Diagnostic models for fever of unknown origin based on 18F-FDG PET/CT: a prospective study in China

BackgroundThis study aims to analyze the 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) characteristics of different causes of fever of unknown origin (FUO) and identify independent predictors to develop a suitable diagnostic model for distinguishing between these causes. A total of 524 patients with classical FUO who underwent standard diagnostic procedures and PET/CT were prospectively studied. The diagnostic performance of PET/CT imaging was analyzed, and relevant clinical parameters that could improve diagnostic efficacy were identified. The model was established using the data of 369 patients and the other 155 patients comprised the validation cohort for verifying the diagnostic performance of the model.ResultsThe metabolic characteristics of the “hottest” lesion, the spleen, bone marrow, and lymph nodes varied for various causes. PET/CT combined with clinical parameters achieved better discrimination in the differential diagnosis of FUO. The etiological diagnostic models included the following factors: multisite metabolic characteristics, blood cell counts, inflammatory indicators (erythrocyte sedimentation rate, C-reactive protein, serum ferritin, and lactate dehydrogenase), immunological indicators (interferon gamma release assay, antinuclear antibody, and anti-neutrophil cytoplasm antibody), specific signs (weight loss, rash, and splenomegaly), and age. In the testing cohort, the AUCs of the infection prediction model, the malignancy diagnostic model, and the noninfectious inflammatory disease prediction model were 0.89 (95% CI 0.86–0.92), 0.94 (95% CI 0.92–0.97), and 0.95 (95% CI 0.93–0.97), respectively. The corresponding AUCs for the validation cohort were 0.88 (95% CI 0.82–0.93), 0.93 (95% CI 0.89–0.98), and 0.95 (95% CI 0.92–0.99), respectively.Conclusions18F-FDG PET/CT has a certain level of sensitivity and accuracy in diagnosing FUO, which can be further improved by combining it with clinical parameters. Diagnostic models based on PET/CT show excellent performance and can be used as reliable tools to discriminate the cause of FUO.Trial registration This study (a two-step method apparently improved the physicians’ level of diagnosis decision-making for adult patients with FUO) was registered on the website http://www.clinical-trials.gov on January 14, 2014, with registration number NCT02035670.

A retrospective analysis of 3 156 admissions with fever of unknown origin in a large Italian hospital

&#x0D; Background: fever of unknown origin (FUO) is defined as a fever with no etiologic diagnosis after standardized investigations performed during 3 days in hospital or after at least 3 ambulatory visits. Our study aims to describe the epidemiology of classic FUO through the retrospective analysis of 902 861 admissions to a large University Hospital in Italy, to investigate its temporal trend, and to evaluate differences between young and old patients.&#x0D; Methods: we retrieved data records of all the admissions between the 1st January 1988 and 31st December 2007. Proportional admission rate (PAR ) of FUO was calculated. Time trends of FUO admissions were analysed by joinpoint regression, with time changes expressed as Expected Annual Percent Change (EA PC). The ICD 9-CM code was used to identify the diagnosis on discharge of FUO cases.&#x0D; Results: in the study period 3 156 patients were admitted with a diagnosis of FUO (PAR=3.50 per 1 000). The time-trend analysis showed two joinpoints, the first in 1995 (EAPC of 307.80, 95% CI: 89.66-776.84, p=0.002), and the second in 1998 (EAPC=-8.57, 95% CI: -10.37-6.73; p&lt;0.001). Around 22% of admissions remained without a definitive diagnosis of FUO, with this percentage being lower in patients ≥65 years compared with subjects aged 21-64.&#x0D; Conclusions: FUO is a leading cause of admission to hospitals, as well as of morbidity and mortality, thus representing a challenge for diagnostic medicine and hospital care. It is necessary to develop a diagnostic methodology for FUO , so as to reduce costs of preventable hospitalizations.&#x0D;

Clinical Features of Spontaneous Remission in the Classic Fever of Unknown Origin: A Retrospective Study

ObjectiveTo summarize the clinical features of spontaneous remission in classic fever of unknown origin (FUO). MethodsMedical records of 121 patients diagnosed with FUO at admission in Peking Union Medical College Hospital between January 2018 and June 2018 were reviewed retrospectively. Patients who were discharged without etiological diagnoses were followed for 2 years. The clinical features and outcomes of these patients were summarized. Multivariate logistic regression was used to analyze related factors of spontaneous remission of FUO. ResultsAfter excluding 2 patients who lost to follow-up, the etiology of 119 FUO patients were as follows: infectious diseases in 30 (25.2%) cases, connective tissue diseases in 28 (23.5%) cases, tumor diseases in 8 (6.7%) cases, other diseases in 6 (5.0%) cases, and unknown diagnoses in 47 (39.5%) cases. Totally, 41 patients experienced spontaneous remission of fever (the median time from onset to remission was 9 weeks, ranging from 4 to 39 weeks). In patients with spontaneous remission in FUO, lymphadenopathy was less common clinical manifestation, the levels of inflammatory markers including leukocyte count, neutrophil count, neutrophil ratio, C-reactive protein, and ferritin were lower, and the proportion of CD8 positive T lymphocytes expressing CD38 was lower. Multivariate logistic regression analysis of factors with a P-value < 0.05 in univariate analysis shown that white blood cell count (OR: 0.545, 95%CI: 0.306-0.971, P = 0.039), neutrophil count (OR: 2.074, 95%CI: 1.004-4.284, P = 0.049), and proportion of neutrophils (OR: 0.928, 95%CI: 0.871-0.990, P = 0.022) were independent significant factors associated with spontaneous remission in FUO. ConclusionsThis study suggested that most patients discharged with undiagnosed classic FUO would remit spontaneously. Thus, for patients with stable clinical conditions, follow-up and observation could be the best choice. Patients with lower level of some inflammatory factors may have a high likelihood of spontaneous remission in classic FUO.

Positron Emission Tomography with Computed Tomography in Evaluations of Classical Fever of Unknown Origin and Length of Hospitalization: A 10-Year Medical Record Review of a Tertiary Hospital.

Positron emission tomography with computed tomography (PET/CT) has proven its value for the differential diagnosis of fever of unknown origin (FUO). However, the extent to which PET/CT during FUO evaluation can shorten the length of hospital stay (LOS) remains unclear. A retrospective review of the medical records over a 10-year period from January 2009 to December 2018 of a tertiary university hospital was performed. The inclusion criteria were symptoms with fever persisting for >3 weeks before admission, as defined in classical FUO. Medical records in which PET/CT was performed after the final diagnosis, such as neoplastic causes, were excluded. Moreover, in the neoplasm category evaluated using PET/CT, only diagnostic PET/CT cases were enrolled; PET/CT cases for confirming metastasis or staging were excluded. Final diagnoses were categorized as infection, neoplasm, noninfectious non-neoplastic inflammatory disorder, miscellaneous, and uncategorizable. Each category was separated into evaluation with and without PET/CT for statistical analyses. In total, 91 patients underwent evaluation for FUO and about one in three underwent PET/CT. Overall LOS was not different between the PET/CT and non-PET/CT groups; however, there were differences in LOS within the categories. For infectious causes, the mean LOS was 21.1 and 11.1 days in the PET/CT and non-PET/CT groups, respectively (P = 0.022). For neoplastic causes, the mean LOS was 11.4 and 36.0 days in the PET/CT and non-PET/CT groups, respectively (P = 0.02). Most patients with FUO were aged 50 - 60 years, and their family and work roles were crucial. A lower LOS may benefit both the patients' families and society at large. Interestingly, PET/CT may contribute to shortening the LOS during FUO evaluation when the causes are neoplastic, by approximately 24 days.

Application of Machine Learning for the Prediction of Etiological Types of Classic Fever of Unknown Origin.

Background: The etiology of fever of unknown origin (FUO) is complex and remains a major challenge for clinicians. This study aims to investigate the distribution of the etiology of classic FUO and the differences in clinical indicators in patients with different etiologies of classic FUO and to establish a machine learning (ML) model based on clinical data.Methods: The clinical data and final diagnosis results of 527 patients with classic FUO admitted to 7 medical institutions in Chongqing from January 2012 to August 2021 and who met the classic FUO diagnostic criteria were collected. Three hundred seventy-three patients with final diagnosis were divided into 4 groups according to 4 different etiological types of classical FUO, and statistical analysis was carried out to screen out the indicators with statistical differences under different etiological types. On the basis of these indicators, five kinds of ML models, i.e., random forest (RF), support vector machine (SVM), Light Gradient Boosting Machine (LightGBM), artificial neural network (ANN), and naive Bayes (NB) models, were used to evaluate all datasets using 5-fold cross-validation, and the performance of the models were evaluated using micro-F1 scores.Results: The 373 patients were divided into the infectious disease group (n = 277), non-infectious inflammatory disease group (n = 51), neoplastic disease group (n = 31), and other diseases group (n = 14) according to 4 different etiological types. Another 154 patients were classified as undetermined group because the cause of fever was still unclear at discharge. There were significant differences in gender, age, and 18 other indicators among the four groups of patients with classic FUO with different etiological types (P < 0.05). The micro-F1 score for LightGBM was 75.8%, which was higher than that for the other four ML models, and the LightGBM prediction model had the best performance.Conclusions: Infectious diseases are still the main etiological type of classic FUO. Based on 18 statistically significant clinical indicators such as gender and age, we constructed and evaluated five ML models. LightGBM model has a good effect on predicting the etiological type of classic FUO, which will play a good auxiliary decision-making function.

Place of the 18F-FDG-PET/CT in the Diagnostic Workup in Patients with Classical Fever of Unknown Origin (FUO).

Objective: To explore the diagnostic contribution of the 18F-FDG-PET/CT in a population of patients with classical fever of unknown origin (FUO), to pinpoint its place in the diagnostic decision tree in a real-life setting, and to identify the factors associated with a diagnostic 18F-FDG-PET/CT. Method: All adult patients (aged ≥ 18 years) with a diagnosis of classical FUO who underwent an 18F-FDG-PET/CT in the University Hospital of Montpellier (France) between April 2012 and December 2017 were included. True positive 18F-FDG-PET/CT, which evidenced a specific disease causing FUO, were considered to be contributive. Results: Forty-four patients with FUO have been included (20 males, 24 females; mean age 57.5 ± 17.1 years). Diagnoses were obtained in 31 patients (70.5%), of whom 17 (38.6%) had non-infectious inflammatory diseases, 9 had infections (20.5%), and 3 had malignancies (6.8%). 18F-FDG-PET/CT was helpful for making a final diagnosis (true positive) in 43.6% of all patients. Sensitivity and specificity levels were 85% and 37%, respectively. A total of 135 investigations were performed before 18F-FDG-PET/CT, mostly CT scans (93.2%) and echocardiography (59.1%), and 108 after 18F-FDG-PET/CT, mostly biopsies (including the biopsy of a temporal artery) (25%) and MRIs (34%). In multivariate analysis, the hemoglobin level was significantly associated with a helpful 18F-FDG-PET/CT (p = 0.019, OR 0.41; 95% CI (0.20–0.87)), while the CRP level was not associated with a contributive 18F-FDG-PET/CT. Conclusion: 18F-FDG-PET/CT may be proposed as a routine initial non-invasive procedure in the diagnostic workup of FUO, especially in anemic patients who could be more likely to benefit from 18F-FDG-PET/CT.

The yield of F18 FDG PET-CT for the investigation of fever of unknown origin, compared with diagnostic CT

Background18F-Fluoro-2-deoxy-D-glucose (FDG) positron emission tomography, with contrast enhanced CT (PET-CT), is recommended as a first or a second-line imaging method for the evaluation of patients with fever of unknown origin (FUO). We evaluated the yield of PET-CT vs. contrast enhanced CT (alone) for the diagnosis of classical FUO. MethodsA single center, 8-year retrospective cohort study. All hospitalized patients who underwent PET-CT for the investigation of classical FUO between 1/2012-1/2020 were included. The final diagnosis, based on clinical, microbiological, radiological and pathological data available at the latest follow-up, at least six months after discharge, was determined. For each case, we determined whether the diagnosis would have been reached based on the CT scan alone, or based on the PET-CT (thus, defining PET-CT as necessary). We compared the overall sensitivity and specificity results for both PET-CT and CT scan. Variables that were found to be significantly associated with PET-CT necessity on univariable analysis were entered into a multivariable logistic regression analysis. The results of the regression model were reported in odds ratios (OR) and 95% confidence intervals (CI). ResultA total of 303 patients with classical FUO were referred for PET-CT. The final diagnoses included infectious diseases in 111/303 patients (36.5%), malignancies in 56/303 patients (18.4%) and non-infectious inflammatory conditions in 52/303 patients (17.1%). FUO resolved without diagnosis in 84/303 patients (28%). The overall sensitivity and specificity of the PET-CT scans were 88.7% and 80.9%, respectively, and for the CT scans were 75.2% and 90.2%, respectively. PET-CT had superior sensitivity vs CT (p=0.00) for all subgroups, with generally decreased specificity than CT for infections and inflammatory conditions. PET-CT was determined as necessary in 26% (79/303) of the patients. Endovascular infection, hematological malignancy and large vessel vasculitis were the only factors associated with PET-CT necessity on multivariable analysis. ConclusionsPET-CT offers superior sensitivity with slightly decreased specificity for the diagnosis of classical FUO compared to diagnostic CT. We recommend PET-CT as the imaging modality of choice for patients with classical FUO, when endovascular infection, hematological malignancy or large vessel vasculitis are suspected.

Fever of Unknown Origin: An Overview of the Diagnostic Approach

Although fever of unknown origin (FUO) was first defined in 1961, it remains a diagnostic challenge. The revised 1991 definition categorized FUO into classic FUO, nosocomial FUO, neutropenic FUO, and human immunodeficiency virus-related FUO, each requiring at least three outpatient visits or 3 days of in-hospital stay. The causes of classic FUO differ greatly geographically and temporally, and are divided into infections, noninfectious inflammatory diseases, neoplasms, and miscellaneous diseases. A systematic, comprehensive and rational approach is required for appropriate diagnosis. A medical history and physical examination are very important; they may reveal diagnostic clues. Here, we review the literature on the causes and diagnostic approaches of classical FUO.

HMGB1, anti-HMGB1 antibodies, and ratio of HMGB1/anti-HMGB1 antibodies as diagnosis indicator in fever of unknown origin

To evaluate the feasibility of serum HMGB1, anti-HMGB1 antibodies, and HMGB1/anti-HMGB1 ratio as a diagnosis indicator of initial clinical classification in patients with fever of unknown origin (FUO). Ninety-four patients with classical FUO and ninety healthy controls were enrolled in this study. The subjects’ clinical data and serum were collected. The serum concentration of HMGB1 was detected by a commercial HMGB1 ELISA kit, while the serum concentration of anti-HMGB1 antibodies were detected by an in-house built anti-HMGB1 antibodies ELISA kit and further confirmed by immunoblotting. According to the hospital diagnosis on discharge, ninety-four FUO patients were divided into four groups, Infectious disease subgroup, autoimmune disease subgroup, malignant tumor subgroup, and undetermined subgroup. The concentrations of HMGB1 in the infectious disease subgroup and autoimmune disease subgroup were higher than those in the malignant tumor subgroup, undetermined subgroup, and healthy control group. The concentration of anti-HMGB1 antibodies in autoimmune disease subtype group was higher than those in other subgroups as well as healthy control group. According to the distribution of HMGB1 and anti-HMGB1 in scatter plots of the patients with FUO, we found that the ratio of serum HMGB1/anti-HMGB1 is an ideal clinical indicator for differential diagnosis of different subtypes of FUO. The best cut-off was 0.75, and the sensitivity, specificity, and AUC were 66.67%, 87.32%, and 0.8, respectively. Correlation analysis showed that serum concentration of HMGB1 was moderately correlated with CRP in infectious diseases subgroup, and the serum concentration of anti-HMGB1 antibodies was strongly correlated with erythrocyte sedimentation rate in autoimmune disease subgroup. Our study had showed that serum HMGB1/anti-HMGB1 antibodies ratio can help clinicians identify FUO subtypes, thereby avoiding many unnecessary examinations and tests, and improving the effectiveness of clinical diagnosis and treatment of FUO.

Classic fever of unknown origin: Analysis of a cohort of 87 patients according to the definition with qualitative study criterion

ObjectivesThe aim of this study was to evaluate the characteristics of fever of unknown origin (FUO) according to the definition with qualitative study criterion and of patients without diagnosis. Materials and methodsProspective observational study performed from 2009 to 2017 of all patients who were diagnosed with FUO according to the extended definition with qualitative study criterion. Demographic, clinical, diagnostic and evolving variables were evaluated. ResultsOf the 87 patients registered, 17.3% presented criteria of inflammation of unknown origin (IUO). The diagnoses were: non-infectious inflammatory diseases (NIID) in 19 patients (21.8%), infections in 15 (17.2%), miscellaneous in 14 (16.1%), malignant diseases in 13 (15%) and without diagnosis in 26 (29.9%). In 17.6% of the cases, a potentially diagnostic clue (PDC) was identified. The patients without diagnosis were characterized by a lower number of total PDC (5.9 ± 3.3 vs. 8.7 ± 3.4; P = .000), fewer clinical signs (.4 ± .6 vs. .9 ± .8; P = .001), a smaller number of tests in the previous study (2.7 ± 2.1 vs. 4.6 ± 2; P = .000), a shorter diagnostic interval (14.6 ± 7.7 days vs. 21.4 ± 9.5 days; P = .029) and less alteration of erythrocyte sedimentation rate (52.3 ± 41.3 mm/h vs. 89.8 ± 42.7 mm/h; P = .000), haemoglobin (12.9 ± 1.7 g/dl vs. 11.7 ± 1.6 g/dl; P = .003) and albumin (36.9 ± 6.4 g/l vs. 33.2 ± 7.2 g/l; P = .025). 18F-fluorodeoxyglucose positron-emission tomography combined with computed tomography (18F-FDG-PET/TC) proved to be helpful in 37% of the cases. Mortality was 6.8%. ConclusionsThe definition of FUO with qualitative study criterion incorporates a diagnostic protocol that provides clear benefits in terms of cost-effectiveness.

Gallium citrate-67 single-photon emission computed tomography/computed tomography for localizing the foci of classic fever and inflammation of unknown origin: A retrospective study of diagnostic yield.

Only few studies have assessed the use of gallium citrate-67 single-photon emission computed tomography/computed tomography (67Ga-SPECT/CT) for localizing the foci of classic fever of unknown origin (FUO) and inflammation of unknown origin (IUO). Hence, the current study aimed to assess the diagnostic contribution of 67Ga-SPECT/CT in a tertiary referral setting where nuclear imaging tests are performed after an unsuccessful comprehensive primary diagnostic workup. We retrospectively assessed the medical records of 27 adult patients with FUO/IUO who had an unsuccessful diagnostic workup and who underwent 67Ga-SPECT/CT for the localization of FUO/IUO foci in our university hospital between 2013 and 2019. The primary outcome was diagnostic yield. The secondary outcomes were overall clinical efficacy and spontaneous remission of FUO/IUO symptoms in patients with a negative 67Ga-SPECT/CT finding. Almost all patients completed the recommended diagnostic workup, except for urine culture and abdominal ultrasonography. Moreover, prior to 67Ga-SPECT/CT, all patients underwent thoraco-abdominopelvic CT scan, which was a non-diagnostic procedure. After a median follow-up of 843 days, the cause was identified in 16 (59%) patients. 67Ga-SPECT/CT successfully localized the FUO/IUO foci in eight patients (diagnostic yield = 30%; 95% confidence interval [CI]: 14%-50%). However, the causes remained unknown during follow-up in 11 (41%) patients. Among them, five experienced spontaneous regression of symptoms. 67Ga-SPECT/CT was negative in four of the five patients with spontaneous regression in symptoms without a definite cause. Considering this an important event, the overall clinical efficacy of 67Ga-SPECT/CT increased to 44% (95% CI: 25%-65%). 67Ga-SPECT/CT had an acceptable diagnostic yield for the localization of FUO/IUO foci, which are challenging to diagnose, in a contemporary tertiary referral care setting. In patients who experienced spontaneous regression in symptoms with an unexplained cause, the absence of abnormal uptake might indicate prospective spontaneous remission. Thus, 67Ga-SPECT/CT could be an active first-line nuclear imaging modality in settings where fluorine-18-fluorodeoxy glucose positron emission tomography and computed tomography is not available for the assessment of FUO/IUO causes.

Diagnostic Value of 18F-FDG-PET/CT in Patients with FUO.

Conventional diagnostic imaging is often ineffective in revealing the underlying cause in a considerable proportion of patients with fever of unknown origin (FUO). The aim of this study was to assess the diagnostic value of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in patients with FUO. We retrospectively reviewed 18F-FDG-PET/CT scans performed on 50 consecutive adult patients referred to our department for further investigation of classic FUO. Final diagnosis was based on histopathological and microbiological findings, clinical criteria, or clinical follow-up. Final diagnosis was established in 39/50 (78%) of the patients. The cause of FUO was infection in 20/50 (40%), noninfectious inflammatory diseases in 11/50 (22%), and malignancy in 8/50 (16%) patients. Fever remained unexplained in 11/50 (22%) patients. 18F-FDG-PET/CT scan substantially contributed to the diagnosis in 70% of the patients, either by identifying the underlying cause of FUO or by directing to the most appropriate site for biopsy. Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of 18F-FDG-PET/CT for active disease detection in patients with FUO were 94.7%, 50.0%, 84.0%, 85.7%, and 75.0%, respectively. In conclusion, whole-body 18F-FDG-PET/CT is a highly sensitive method for detection of the underlining cause of FUO or for correctly targeting suspicious lesions for further evaluation.

Retrospective analysis of 1,641 cases of classic fever of unknown origin

BackgroundFever 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. It is a special type of fever and a common disease in internal medicine. However, due to its complex etiology, lack of characteristic clinical manifestations, and insufficient laboratory examination indicators, it often baffles clinicians in diagnosis. We herein present a study of the etiological factors and clinical features of classic fever of unknown origin (FUO) to provide help for related clinical diagnosis and treatment.MethodsA total of 1,641 cases of patients with classic FUO hospitalized in West China Hospital of Sichuan University between January 1, 2011 and December 31, 2017, were collected, and the etiological factors of classic FUO were analyzed. A special effort was made to explore and screen the laboratory indicators related to infectious diseases, and the above data were compared with the clinical features of tuberculosis and lymphoma, which are difficult to diagnose.ResultsAmong the 1,641 patients, 1,504 were finally diagnosed through various types of examination or diagnostic methods, and the diagnosis rate was 91.65%. Among all the causes of the 1,641 cases of FUO, 48.69% [799] were infectious diseases, of which tuberculosis was the most common, accounting for 19.50% [320]. Connective tissue diseases were responsible for 19.26% [316] of cases, of which adult-onset Still’s disease (AOSD) was the most common, comprising 89 (5.42%) of the cases; 16.94% [278] were neoplastic diseases, and lymphoma (143, 8.71%) cases, was the most common malignant tumor; 6.76% [111] were other diseases; and in 8.35% [137] of cases, the cause was unclear. Through comparative analysis of tuberculosis and lymphoma, no significant differences were found between the symptoms, signs, and non-specific routine examination results of the two diseases. The diagnosis of these diseases was more dependent on tuberculosis-related examinations and pathological examinations.ConclusionsInfectious diseases are the principal cause of classic FUO, in which tuberculosis accounts for a large proportion. Non-infectious diseases that cause FUO are mainly connective tissue diseases and malignant tumors. Of the various causes of classic FUO, tuberculosis and lymphoma are relatively difficult to diagnose. In most cases, the causes of classic FUO can be ascertained.