Diagnosis Of Fever Of Unknown Origin Research Articles

The value of metagenomic next-generation sequencing in the diagnosis of fever of unknown origin

Fever of unknown origin (FUO) caused by infection is a disease state characterized by complex pathogens and remains a diagnostic dilemma. Metagenomic next-generation sequencing (mNGS) technology is a promising diagnostic tool for identifying pathogenic microbes of FUO caused by infection. Little is known about the clinical impact of mNGS in the etiological diagnosis of FUO. This study focuses on the value of mNGS in the etiologic diagnosis of FUO by diagnostic performance, further clarifying the value of mNGS in clinical management. In a single-centre retrospective cohort study, 263 FUO patients who underwent both mNGS and culture at the First Affiliated Hospital of Nanchang University were enrolled from December 2020 to February 2023. The sensitivity and specificity of culture and mNGS were analyzed based on the final clinical diagnosis as the gold standard to assess the diagnostic value of mNGS in FUO cases. Among the 263 patients, 69.96%(184/263) cases were diagnosed as infectious diseases, of which lower respiratory tract infections were the most common, accounting for 53.26%(98/184). 30.04%(79/263) cases had a diagnosis of non-infectious disease. From these cases, mNGS identified 150 true-positive cases, 21 false-positive cases, 58 true-negative cases, and 34 false-negative cases. The sensitivity of mNGS in infection diagnosis was much higher than that of culture [81.52%(150/184) vs. 47.28%(87/184)], but the specificity was the opposite[73.42%(58/79) vs. 84.81%(67/79)]. mNGS had a receiver operating characteristic (ROC) curve of 0.775 for infectious disease, which was significantly higher than that of culture (0.661, P < 0.05). mNGS detection revealed that bacteria were the most commonly identified potential pathogens. The top causative pathogens identified were Acinetobacter baumannii. Of the 263 patients with FUO, clinical management of 48.67% (128/263) patients was positively affected by mNGS, and 51.33% (135/263) patients were not affected by mNGS(P = 0.1074). To sum up, infectious diseases are the principal cause of FUO. mNGS could significantly improve the detected pathogen spectrum of FUO caused by infection. However, the FUO disease spectrum is relatively broad, including a large number of non-infectious diseases. Therefore, Further investigation is warranted into the specific clinical scenarios for which mNGS may offer the greatest clinical diagnostic value.

Performance and value of 18F‑FDG PET/CT in patients with fever of unknown origin.

Fever of unknown origin (FUO) is a common clinical and diagnostic challenge. The main aim of the present study was to evaluate the diagnostic accuracy of 18F-fluorodeoxyglucose (18FDG) positron emission tomography (PET)/CT in patients who present with FUO. Overall, 105 consecutive patients (61 men and 44 women) with a mean age of 51±35 years with FUO underwent 18FDG PET/CT scans. The performance of 18FDG PET/CT in determining the etiology of FUO was assessed. According to the PET/CT results, patients were classified into four groups: Group 1, patients with true-positive results (n=51; 49%), in whom abnormal 18FDG uptake identified the final diagnosis; group 2, patients with false-positive results (n=24; 23%), in whom 18FDG uptake was not consistent with the final diagnosis; group 3, patients with true-negative results (n=10; 9.5%), in whom the 18FDG uptake was normal and no final disease was established; and group 4, patients with false-negative results (n=20; 19%), in whom 18FDG uptake was normal and disease was finally established. Of the 51 patients with true-positive PET/CT results, 51% had infections, 35% had malignancies and 14% had inflammatory processes. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 72, 29, 68, 33 and 58%, respectively. In conclusion, the present results demonstrated that 18FDG PET/CT established the final diagnosis of FUO in the majority of patients (72%). These results support the use of 18FDG PET/CT in the initial evaluation and management of patients with FUO.

An uncommon diagnosis of a young female with fever of unknown origin (FUO): Idiopathic Hemophagocytic Lymphohistiocytosis (HLH)

Background. Hemophagocytic Lymphohistiocytosis (HLH), characterized by the uncontrolled activation of immune cells leading to a hyperinflammatory state, is seldom considered in the initial differential diagnosis of FUO. The rarity of idiopathic HLH, especially in young individuals without an identifiable trigger, emerges as an uncommon and particularly challenging diagnosis. This case report presents a compelling narrative of a young female grappling with the complexities of FUO, ultimately revealing the rare and life-threatening entity of idiopathic HLH. Case report. A 25 year old female was referred to our hospital in view of persistent high grade fever since 3 months. Patient has no other complaints. Vitals stable. General and systemic examination normal. Lab investigations showed a total leukocyte count 18000 cell/μL, hemoglobin 9.2 g/dL, and platelets 68000 cells/μL. Other blood investigations showed erythrocyte sedimentation rate (ESR) 88 mm/h, C-reactive protein 21 mg/L, ferritin 670 ng/mL, triglyceride 281 mg/dL, and fibrinogen 1.2g/L. She also had transaminitis with AST 80, ALT 92 and ALP 1442. The entire infectious diseases panel was done which came negative for all, including viral serologies and hepatitis markers. Procalcitonin level was normal and no other relevant investigations came positive. Autoimmune panel analysis also came negative. Blood cultures came negative in two different samples. Also, there is no evidence of vegetation in echocardiography. Coming to the invasive investigations, bone marrow biopsy and aspiration were done to arrive at a diagnosis and it showed hemophagocytosis. Endoscopy and colonoscopy were done, which came normal. CT thorax and abdomen also showed no significant abnormalities, ruling out the probability of missing any gross malignancies. After all this extensive work up and according to Hscore, which is used to estimate an individual’s risk of having reactive hemophagocytic syndrome, this patient was diagnosed with HLH. According to the current HLH guidelines, initial treatment for the disease consists of etoposide, corticosteroids (dexamethasone), or cyclosporine given for 8 weeks. The patient was started on the same above treatment regimen, but only with corticosteroids for a period of 8 weeks, after a consultation with the hematologist. No recurrence is seen in her 6-months of follow-up. The regimen was well tolerated by the patient. Studies also have shown that therapeutic plasma exchange also has a role in HLH treatment, which can be tried in familial and relapsing cases. Conclusion. In our case, this young female was diagnosed to have idiopathic HLH, after ruling out all the familial and secondary causes of HLH including infections, malignancy and autoimmune diseases. The patient was also started on treatment early after the bone marrow and other relevant investigations according to HScore suggested the diagnosis of HLH and the patient improved accordingly. Hence, apart from clearly knowing the etiology or clinical manifestations, HLH is associated with a high mortality rate if appropriate treatment not given. Generally, the underlying etiology determines the prognosis of the disease. But, it is not a good idea to delay the treatment in order to find the cause and type of HLH, because the exhaustive work up might lead to unacceptable delays in improvement and prognosis of the patient. The diagnostic work up and treatment should be done simultaneously in the patient, which has been done in our case and it lead to a good outcome. Though HLH is a fatal and dangerous disease and also highly challenging to make a diagnosis due its uncommon and largely variable clinical presentation, smart work up and early initiation of treatment will lead to better prognostic outcomes.

Role of 18 F-FDG PET/CT for providing a targeted approach for etiology of PUO.

This study aimed to evaluate the potential role of 18F-fluorodeoxyglucose PET/computed tomography (18F-FDG PET/CT) in providing a targeted approach for diagnosing the etiology of Pyrexia of Unknown Origin (PUO). A total of 573 PUO patients were included in this ambispective study, with a mean age of 39.40 ± 4.6 years. Patients underwent FDG PET/CT scans using dedicated hybrid scanners. PET/CT data were interpreted by experienced nuclear medicine physicians. The study analyzed the guidance provided by FDG PET/CT for appropriate biopsy sites and assessed concordance between PET/CT findings and histopathological examination. Out of the 573 patients, a final diagnosis was reached for 219 patients, including malignancy, infectious causes, noninfectious inflammatory causes (NIID), and precancerous conditions. FDG PET/CT played a crucial role in guiding clinicians to appropriate biopsy sites, contributing to a higher diagnostic yield. Concordance between PET/CT findings and histopathological examination emphasized the noninvasive diagnostic potential of PET/CT in identifying underlying causes of PUO. Overall, FDG PET/CT contributed to guiding the appropriate site of biopsy or concordance of the first differential diagnosis with the final diagnosis in 50.05% of cases. This study highlights the valuable role of FDG PET/CT in providing a targeted approach for diagnosing PUO, showcasing its potential in guiding clinicians towards appropriate biopsy sites and improving the diagnostic yield. The findings underscore the importance of integrating FDG PET/CT into the diagnostic pathway for PUO, ultimately enhancing patient management and outcomes. Further prospective studies are necessary to validate these results and refine the integration of FDG PET/CT in the diagnosis of PUO.

Fever management in children and insights into fever of unknown origin: a survey among Italian pediatricians.

Fever is a common symptom in children, but despite existing guidelines, pediatricians may not fully apply recommendations. Fever of Unknown Origin (FUO) is generally referred to as an unexplained prolonged fever. However, a standardized FUO definition and management is missing. To collect updated data on the approach to fever and FUO among Italian pediatricians. A cross-sectional anonymous survey was conducted among a large sample of primary care and hospital pediatricians. The panel group formulated and proposed a practical FUO definition, using a modified Delphi approach. A 75% consensus was required to reach an agreement. Among 620 respondents, paracetamol was the first-choice antipyretic for 97.7% of participants, followed by ibuprofen; 38.4% prescribed antipyretics based on a specific body temperature rather than on child's discomfort, while physical methods were almost completely abandoned. Alternate treatment was recommended by 19.8% (123/620) of participants, 16.9% (105/620) would prescribe antipyretics to prevent adverse events following immunization. Regarding FUO diagnosis, 58.3% (362/620) considered as cut-off a body temperature above 38°C; the duration required was one week according to 36.45% (226/620) of participants, two weeks according to 35.32% (219/620). The FUO definition proposed by the expert panel reached 81% of consent. Large agreement was observed on first-level laboratory and instrumental investigations in the diagnostic evaluation of FUO, whereas more discrepancies arose on second and third-level investigations. Compared to what participants reported for the treatment of non-prolonged fever, a significant decrease in the prescription of paracetamol as first-choice drug in children with FUO was observed (80.5%; P < 0.0001). Interestingly, 39% of participants would empirically recommend antibiotics, 13.7% steroids, and 4.5% Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) for persistent FUO. Non-recommended behaviors in fever management persist among pediatricians, including alternating use of paracetamol and ibuprofen, and their prophylactic use for vaccinations. Our data confirm the variability in the definition, work-up, and management of FUO. We observed that in children with FUO paracetamol was significantly less commonly preferred than in non-prolonged fever, which is not supported by evidence. Our findings combined with evidence from existing literature underlined the need for future consensus documents.

Incidence and outcomes of fever of unknown origin after kidney transplant in the modern era.

While presumably less common with modern molecular diagnostic and imaging techniques, fever of unknown origin (FUO) remains a challenge in kidney transplant recipients (KTRs). Additionally, the impact of FUO on patient and graft survival is poorly described. A cohort of adult KTRs between January 1, 1995 and December 31, 2018 was followed at the University of Wisconsin Hospital. Patients transplanted from January 1, 1995 to December 31, 2005 were included in the "early era"; patients transplanted from January 1, 2006 to December 31, 2018 were included in the "modern era". The primary objective was to describe the epidemiology and etiology of FUO diagnoses over time. Secondary outcomes included rejection, graft and patient survival. There were 5590 kidney transplants at our center during the study window. FUO was identified in 323 patients with an overall incidence rate of .8/100 person-years. Considering only the first 3years after transplant, the incidence of FUO was significantly lower in the modern era than in the early era, with an Incidence Rate Ratio (IRR) per 100 person-years of .48; 95% CI: .35-.63; p<.001. A total of 102 (31.9%) of 323 patients had an etiology determined within 90days after FUO diagnosis: 100 were infectious, and two were malignancies. In the modern era, FUO remained significantly associated with rejection (HR=44.1; 95% CI: 16.6-102; p<.001) but not graft failure (HR=1.21; 95% CI: .68-2.18; p=.52) total graft loss (HR=1.17; 95% CI: .85-1.62; p=.34), or death (HR=1.17; 95% CI: .79-1.76; p=.43. FUO is less common in KTRs during the modern era. Our study suggests infection remains the most common etiology. FUO remains associated with significant increases in risk of rejection, warranting further inquiry into the management of immunosuppressive medications in SOT recipients in the setting of FUO.

Integrating Medical Domain Knowledge for Early Diagnosis of Fever of Unknown Origin: An Interpretable Hierarchical Multimodal Neural Network Approach.

Accurate and interpretable differential diagnostic technologies are crucial for supporting clinicians in decision-making and treatment-planning for patients with fever of unknown origin (FUO). Existing solutions commonly address the diagnosis of FUO by transforming it into a multi-classification task. However, after the emergence of COVID-19 pandemic, clinicians have recognized the heightened significance of early diagnosis in patients with FUO, particularly for practical needs such as early triage. This has resulted in increased demands for identifying a wider range of etiologies, shorter observation windows, and better model interpretability. In this paper, we propose an interpretable hierarchical multimodal neural network framework (iHMNNF) to facilitate early diagnosis of FUO by incorporating medical domain knowledge and leveraging multimodal clinical data. The iHMNNF comprises a top-down hierarchical reasoning framework (Td-HRF) built on the class hierarchy of FUO etiologies, five local attention-based multimodal neural networks (La-MNNs) trained for each parent node of the class hierarchy, and an interpretable module based on layer-wise relevance propagation (LRP) and attention mechanism. Experimental datasets were collected from electronic health records (EHRs) at a large-scale tertiary grade-A hospital in China, comprising 34,051 hospital admissions of 30,794 FUO patients from January 2011 to October 2020. Our proposed La-MNNs achieved area under the receiver operating characteristic curve (AUROC) values ranging from 0.7809 to 0.9035 across all five decomposed tasks, surpassing competing machine learning (ML) and single-modality deep learning (DL) methods while also providing enhanced interpretability. Furthermore, we explored the feasibility of identifying FUO etiologies using only the first N-hour time series data obtained after admission.

Early application of metagenomics next-generation sequencing may significantly reduce unnecessary consumption of antibiotics in patients with fever of unknown origin

BackgroundMetagenomic next-generation sequencing (mNGS) is a novel nucleic acid method for the detection of unknown and difficult pathogenic microorganisms, and its application in the etiological diagnosis of fever of unknown origin (FUO) is less reported. We aimed to comprehensively assess the value of mNGS in the etiologic diagnosis of FUO by the pathogen spectrum and diagnostic performance, and to investigate whether it is different in the time to diagnosis, length of hospitalization, antibiotic consumption and cost between FUO patients with and without early application of mNGS.MethodsA total of 149 FUO inpatients underwent both mNGS and routine pathogen detection was retrospectively analyzed. The diagnostic performance of mNGS, culture and CMTs for the final clinical diagnosis was evaluated by using sensitivity, specificity, positive predictive value, negative predictive value and total conforming rate. Patients were furtherly divided into two groups: the earlier mNGS detection group (sampling time: 0 to 3 days of the admission) and the later mNGS detection group (sampling time: after 3 days of the admission). The length of hospital stay, time spent on diagnosis, cost and consumption of antibiotics were compared between the two groups.ResultsCompared with the conventional microbiological methods, mNGS detected much more species and had the higher negative predictive (67.6%) and total conforming rate (65.1%). Patients with mNGS sampled earlier had a significantly shorter time to diagnosis (6.05+/-6.23 vs. 10.5+/-6.4 days, P < 0.001) and days of hospital stay (13.7+/-20.0 vs. 30.3 +/-26.9, P < 0.001), as well as a significantly less consumption (13.3+/-7.8 vs. 19.5+/-8.0, P < 0.001) and cost (4543+/-7326 vs. 9873 +/- 9958 China Yuan [CNY], P = 0.001) of antibiotics compared with the patients sampled later.ConclusionsmNGS could significantly improve the detected pathogen spectrum, clinical conforming rate of pathogens while having good negative predictive value for ruling out infections. Early mNGS detection may shorten the diagnosis time and hospitalization days and reduce unnecessary consumption of antibiotics.

The role of bone marrow biopsy in patients with pyrexia of unknown origin

Background: Pyrexia of unknown origin (PUO) is a major complication which remains undiagnosed. Different diagnostic test were used to arrive at final investigation. Bone marrow biopsy (BMB) plays a vital role in diagnosis of PUO. The objective of current study was to determine the role of bone biopsy in diagnosing various types of causes of pyrexia of unknown origin.&#x0D; Patients and methods: A prospective cross-sectional study was conducted from 1st September 2018 to 28th February 2019 at Department of Hematology, Combined Military Hospital Lahore, Pakistan. The data of 120 patients who were remained undiagnosed for at least 1 week were enrolled. Standard procedures were used to obtain the biopsy specimens and bone marrow aspiration was sent for microbiological examination. All the demographic information was kept on a structured self-designed proforma. Data was entered and analyzed using SPSS v.24.&#x0D; Results: Out of 120 patients recruited in the study there were 67 (55.8%) were from age group 16 to 35 years, were males (65.8%) and 65.0% patients were suffering from fever for more than 3 days. The majority of the participants (30%) were diagnosed with infections, fever due to reactive changes (10.0%), acute leukemia (14.2%), lymphoma (11.7%), chronic leukemia (10.0%), aplastic anemia (4.2%), multiple myeloma (2.5%) and 11.7% patients were undiagnosed&#x0D; Conclusion: In the diagnosis of pyrexia of unknown origin, morphological and histological investigation of bone marrow plays a vital role. However, if it is combined with other diagnostic modalities such as radiological, microbiological, and serological examinations, the efficiency of diagnosis can be improved.

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;

Differential Diagnosis of Fever of Unknown Origin in Drug Reaction with Eosinophilia and Systemic Symptom (DRESS)

Objective: To describe an unusual case of drug reaction with eosinophilia and systemic symptoms presenting as fever of unknown origin (FUO) and the diagnostic hurdles that come with the presence of differential diagnosis of FUO, which is tuberculous lymphadenitis. Methods: A 34-year-old female with a chief complaint of fever that has lasted for 3 weeks accompanied with jaundice and skin rashes for 2 weeks was admitted with an indication of FUO. She had a history of carbamazepine consumption for trigerminal neuralgia 2 months prior. Cervical lymphadenopathy was palpable bilaterally and hepatomegaly, elevated liver enzyme, as well as hyperbilirubinemia were observed. After excluding differentials for many causes of prolonged fever, patient was treated for Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) and was given intravenous steroid injections. Fine needle aspiration biopsy was performed for her cervical lymphadenopathy. Results: Biopsy presented a mix of sialadenitis and tuberculous lymphadenopathy. Clinical improvement was observed on the second day after steroid administration. Patient was discharged on the seventh day after steroid administration. Conclusion: FUO is one of the possible manifestations of DRESS; however, thorough investigation still needed to be done considering the possibility of more than one entity of disease that can cause FUO in patients, such as tuberculous lymphadenopathy seen in this case.

Evaluations of Clinical Utilization of Metagenomic Next-Generation Sequencing in Adults With Fever of Unknown Origin.

IntroductionThe diagnosis of infection-caused fever of unknown origin (FUO) is still challenging, making it difficult for physicians to provide an early effective therapy. Therefore, a novel pathogen detection platform is needed. Metagenomic next-generation sequencing (mNGS) provides an unbiased, comprehensive technique for the sequence-based identification of pathogenic microbes, but the study of the diagnostic values of mNGS in FUO is still limited.MethodsIn a single-center retrospective cohort study, 175 FUO patients were enrolled, and clinical data were recorded and analyzed to compare mNGS with culture or traditional methods including as smears, serological tests, and nucleic acid amplification testing (NAAT) (traditional PCR, Xpert MTB/RIF, and Xpert MTB/RIF Ultra).ResultsThe blood mNGS could increase the overall rate of new organisms detected in infection-caused FUO by roughly 22.9% and 19.79% in comparison to culture (22/96 vs. 0/96; OR, ∞; p = 0.000) and conventional methods (19/96 vs. 3/96; OR, 6.333; p = 0.001), respectively. Bloodstream infection was among the largest group of those identified, and the blood mNGS could have a 38% improvement in the diagnosis rate compared to culture (19/50 vs. 0/50; OR, ∞; p = 0.000) and 32.0% compared to conventional methods (16/50 vs. 3/50; OR, 5.333; p = 0.004). Among the non-blood samples in infection-caused FUO, we observed that the overall diagnostic performance of mNGS in infectious disease was better than that of conventional methods by 20% (9/45 vs. 2/45; OR, 4.5; p = 0.065), and expectedly, the use of non-blood mNGS in non-bloodstream infection increased the diagnostic rate by 26.2% (8/32 vs. 0/32; OR, ∞; p = 0.008). According to 175 patients’ clinical decision-making, we found that the use of blood mNGS as the first-line investigation could effectively increase 10.9% of diagnosis rate of FUO compared to culture, and the strategy that the mNGS of suspected parts as the second-line test could further benefit infectious patients, improving the diagnosis rate of concurrent infection by 66.7% and 12.5% in non-bloodstream infection, respectively.ConclusionThe application of mNGS in the FUO had significantly higher diagnostic efficacy than culture or other conventional methods. In infection-caused FUO patients, application of blood mNGS as the first-line investigation and identification of samples from suspected infection sites as the second-line test could enhance the overall FUO diagnosis rate and serve as a promising optimized diagnostic protocol in the future.

Etiology and clinical characteristics of fever of unknown origin in 357 pediatric patients

Objective: To explore the etiologies and clinical characteristics of fever of unknown origin (FUO) and to provide clues for early diagnosis of FUO. Methods: The data about etiology, age, sex, clinical course, length of hospital stays and the expression levels of inflammatory factors in fever phase of 357 pediatric inpatients who were diagnosed with FUO in Children's Hospital of Fudan University from 1 January 2016 to 31 December 2020 were collected and retrospectively analyzed. Participants were grouped into infectious disease, inflammatory disease, malignancy and others and according to the classification of diseases and also grouped into those aged<1 year, 1-<3 years,3-<6 years, 6-<12 years and 12-<18 years. Comparisons between groups were performed using the Mann-Whitney U test, Kruskal-Wallis H test and χ² test. Results: Among the 357 patients (217 males and 140 females). The age of onset was 3.9 (1.3, 9.2) years and visiting age was 5.1 (2.0, 9.3) years. The time-consuming of diagnosis was 94 (66, 213) days. The hospital stay was 8 (6, 14) days. The most frequently identified cause of FUO was infectious diseases (163 cases, 45.7%), followed by non-infectious inflammatory diseases (133 cases, 37.2%), malignancy (21 cases, 5.9%) and others (40 cases, 11.2%). The patients at younger age were more likely to be attacked by malignancy, oncologic diagnoses, and others, nevertheless patients at older age were more likely to be attacked by non-infectious inflammatory diseases oppositely (9.8 (3.6, 11.5) vs. 3.0 (1.2, 7.0), 2.3 (1.0, 5.2), 0.9 (0.5, 1.8) years, U=41.30, 15.94, 37.08, all P<0.01);106 (65%) patients were male, and 57 (35%) patients were female. This result indicated that boys were more susceptible to infectious diseases (χ²=14.73, P<0.01). Analysis of inflammatory factors in serum among 103 patients, interleukin (IL)-6 level in 40 infectious diseases patients (9 (2, 38) ng/L) was significantly lower than those of 6 tumor patients (89 (64, 599) ng/L) and 57 non-infectious inflammatory diseases patients (25 (8, 78) ng/L, U=51.05, 15.70, both P<0.05), no significant difference was observed in IL-2, IL-4, IL-10, tumor necrosis factor α and interferon among the groups (all P>0.05). The patients grouped into those aged 1-<3 years and 3-<6 years were more likely to be attacked by infectious diseases (51.3% (59/115) and 57.1% (40/70)), while patients grouped into those aged 6-<12 years and 12-<18 years were more likely to be attacked by non-infectious inflammatory diseases (55.6% (65/117) and 72.4% (21/29)). Conclusions: Infectious disease is still the main cause of FUO in children and the boys are more susceptible to infectious diseases. However, the morbidity of non-infectious inflammatory diseases increases to number 1 in FUO of children over 6 years of age.

Febrile syndrome in children younger than 29 days

Acute fever of unknown origin (FUO) in children under 29 days is a worrying situation because of the risk of serious bacterial infection (SBI). to study the main clinical and laboratory characteristics of a group of hospitalized children under 29 days with diagnosis of FUO. Retrospective study of children under 29 days hospitalized due to FUO. The clinical records of the patients were reviewed, recording age, sex, history of fever before consultation, temperature at admission, estimated severity at admission and discharge, discharge diagnoses, laboratory tests, and indicated treatments. Patients were classified according to the severity of the discharge diagnosis, as severe (S) and non-severe (NS). The inclusion criteria were term newborn, age less than 29 days, fe ver > 38°C registered at home or admission, and history of < 4 days. 468 children with FUO were admitted. Concordance between severity at admission and discharge was low (Kappa = 0.125; p = 0.0007). 26.1% of children were S and 73.9% NS. In the S group, urinary tract infection domínate (70.5%) and in the NS, FUO (67.6%). The cut-off levels for leukocytes/mm3, C-reactive protein, and neutrophils/mm3 showed negative predictive values to rule out severe bacterial infection. Conclu sions: Most of the newborns presented mild severity at admission, but 24% of them had SBI, thus hospitalization and close clinical observation are always necessary. Laboratory tests, such as CRP, white blood cell and neutrophils count are not good predictors of SBI. Early treatment with antibio tics for patients who meet the low-risk criteria is debatable.

Pyrexia of Unknown Origin in a 1-year-old Child

ABSTRACT Introduction: Pyrexia of unknown origin (PUO) still remains a challenge in paediatric practice. Appropriate history, physical examination, and exhaustive investigations are crucial in managing cases of PUO. Case Presentation: UU, was a 1-year-old female, who was seen at our facility on 16 January 2020, with a 4-day history of fever. Fever was high grade and intermittent. Examination revealed pyrexia of 38°c and no other remarkable findings. Lassa fever virus serology, hepatitis B surface antigen, hepatitis C surface antigen, C-reactive protein, erythrocyte sedimentation rate, full blood count, blood culture (with Bactec), malarial parasite, Mantoux, and CXR were all requested. Results of all these investigations were negative. Echocardiography done showed a 0.23 cm² vegetation at the septal leaflet of the tricuspid valve. A diagnosis of infective endocarditis was made and intravenous vancomycin, ceftriaxone, and metronidazole were commenced. Weekly urinalysis and serum electrolyte urea and creatinine monitoring were documented. After a 3-week course of intravenous antibiotics, patient still had fever with temperature higher than 38°c. A diagnosis of PUO was made and a follow-up plan was to do a bone marrow aspiration to rule out leukaemia and serology to rule out connective tissue disease. Conclusion: In managing a child with PUO, detailed history, appropriate physical examination and exhaustive investigations should be done. This is crucial in that even if diagnosis is not reached, several causes of PUO could have been ruled out.

Fever of unknown origin (FUO) on a land on cross-roads between Asia and Europa; a multicentre study from Turkey.

The differential diagnosis of Fever of Unknown Origin (FUO) is still a major clinical challenge despite the advances in diagnostic procedures. In this multicentre study, we aimed to reveal FUO aetiology and factors influencing the final diagnosis of FUO in Turkey. A total of 214 patients with FUO between the years 2015 and 2019 from 13 tertiary training and research hospitals were retrospectively evaluated. The etiologic distribution of FUO was infections (44.9%), malignancies (15.42%), autoimmune/inflammatory (11.68%) diseases, miscellaneous diseases (8.41%) and undiagnosed cases (19.62%). Brucellosis (10.25%), extrapulmonary tuberculosis (6.54%) and infective endocarditis (6.54%) were the most frequent three infective causes. Solid malignancies (7.1%) and lymphoma (5.6%), adult-onset still's disease (6.07%) and thyroiditis (5.14%) were other frequent diseases. The aetiological spectrum did not differ in elderly people (P<.05). Infections were less frequent in Western (34.62%) compared with Eastern regions of Turkey (60.71%) (P<.001, OR: 0.31, 95% Cl: 0.19 to 0.60). The ratio of undiagnosed aetiology was significantly higher in elderly people (p: 0.046, OR: 2.34, 95% Cl: 1.00 to 5.48) and significantly lower in Western Turkey (P: .004, OR: 3.07, 95% Cl: 1.39 to 6.71). Brucellosis, extrapulmonary tuberculosis and infective endocarditis remain to be the most frequent infective causes of FUO in Turkey. Solid tumours and lymphomas, AOSD and thyroiditis are the other common diseases. The aetiological spectrum did not differ in elderly people, on the other hand, infections were more common in Eastern Turkey. A considerable amount of aetiology remained undiagnosed despite the state-of-the-art technology in healthcare services.

The diagnostic value of 18F-FDG PET/CT in identifying the causes of fever of unknown origin

This study investigated the clinical significance of 18F-fluorodeoxyglucose positron emission tomography / computed tomography (18F-FDG PET/CT) in identifying the causes of fever of unknown origin (FUO). Patients with a fever who received an 18F-FDG PET/CT examination were retrospectively selected. The means of the two groups were compared using an independent-samples t-test. Among the 89 included patients, 66 were diagnosed using 18F-FDG PET/CT. The sensitivity, specificity and diagnostic accuracy of 18F-FDG PET/CT for the diagnosis of patients with FUO were 84.5%, 25.8%, and 64.0%, respectively. The detection rates of 18F-FDG PET/CT for neoplastic diseases, infectious diseases and non-infectious inflammatory diseases were 100%, 61.3%, and 75%, respectively. The difference in C-reactive protein (CRP) levels between the two groups was statistically significant. 18F-FDG PET/CT has great clinical importance in diagnosing and identifying causes of FUO and improves the accuracy of FUO diagnosis when combined with serum CRP levels.

CAN HUMAN TOXOPLASMOSIS BE WITHIN THE DIFFERENTIAL DIAGNOSIS OF FEVER OF UNKNOWN ORIGIN: A CROSS-SECTIONAL STUDY

More than 200 diseases can be represented in differential diagnosis of fever of unknown origin(FUO). The mainstay for the proper diagnosis of FUO took right path for the correct investigations.Globally, Toxoplasma gondii infection persists lifelong within the affected host organs inthe dormant bradyzoites form. Once the host immunity decreases, it can be converted back tothe activate tachyzoite form that attach the host cells. The aim of our study is to estimate thefrequency of toxoplasmosis in patients with fever of unknown origin, concerning the etiology.A cross-sectional study was done from November 2017 to May 2018, including 140 patientschosen with FUO (100 males &40 females), recruited from Port Said Fever Hospital/ Egypt.Their ages ranged between 16 and 70 years old. Patients were subjected to comprehensive historytaking, laboratory investigations, clinical and radiologic examination. Detection of anti-Toxoplasma IgM&IgG antibodies was done by the Electrochemiluminescence immunoassay.Patients had fever with known origin proved by investigations, were excluded from the study.The results showed that 7.1% of the FUO cases were serologically positive for ToxoplasmaIgG. Of them, 80% were females and 20% were males. About 70% of Toxopl-asma-IgG positivecases were represented with fever for 3weeks, and 30% were represented with fever formore than 3weeks. The 70% of the target group had cervical lymphadenopathy and all of themhad hepatosplenomegaly. Moreover, all cases were eating fast food.

Fever of unknown origin

Fever of unknown origin (FUO) is a diagnosis that describes a prolonged febrile illness without an established cause, despite investigations. From the first definition of the medical condition (given by Petersdorf and Beeson in 1961) the diagnostic criteria have changed over time, intending to improve the management and outcome of these patients. The main causes of FUO fall into 4 categories: infectious, non-infectious (inflammatory), neoplastic and diverse causes. The etiology of FUO has changed over time, due to ever-changing disease patterns and the development of diagnostic techniques. A significant percentage of patients with FUO remain without an etiologic diagnosis, despite advanced diagnostic tests. Gathering potentially diagnostic clues through history, physical examination and nonspecific key paraclinical abnormalities is the basis for the diagnosis of FUO.