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Fever has preoccupied physicians since the earliest days of clinical medicine. It has been the subject of scrutiny in recent decades. Historical convention has mostly determined that 37.0°C (98.6°F) should be regarded as normal body temperature, and more modern evidence suggests that fever is a complex physiological response involving the innate immune system and should not be characterized merely as a temperature above this threshold. Fever of unknown origin (FUO) was first defined in 1961 by Petersdorf and Beeson and continues to be a clinical challenge for physicians. Although clinicians may have some understanding of the history of clinical thermometry, how average body temperatures were established, thermoregulation, and pathophysiology of fever, new concepts are emerging. While FUO subgroups and etiologic classifications have remained unchanged since 1991 revisions, the spectrum of diseases, clinical approach to diagnosis, and management are changing. This review considers how newer data should influence both definitions and lingering dogmatic principles. Despite recent advances and newer imaging techniques such as 18-fluorodeoxyglucose–positron emission tomography, clinical judgment remains an essential component of care.Fever of unknown origin subgroups and etiologic classifications have remained unchanged since 1991; however, the spectrum of diseases, clinical approach to diagnosis and management are changing. This review considers how newer data should influence both definitions and lingering dogmatic principles.

Abstract Background Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are syndromes commonly used as medical diagnoses. Since the existing literature has a mixture of diagnostic approaches, developing consensus-based recommendations would be helpful for clinicians, researchers, and patients. Methods A modified Delphi process was performed from October 2022 to July 2023, involving 4 rounds of online surveys and 2 live video conferences. The panel comprised international experts recruited based on peer-reviewed published publications and studies. Results Among 50 invited experts, 26 (52.0%) agreed to participate. Twenty-three panelists completed round 1 of the survey, 21 completed rounds 2 and 3, 20 completed round 4, and 7 participated in round 5 live video discussions. Of the participants, 18 (78.3%) were academic-based clinicians and researchers, 5 (21.7%) practiced in a community-based hospital, and 6 (26.1%) were female. Consensus was reached on 5 themes: (1) incorporating epidemiologic factors, such as geographic location and travel history; (2) updated criteria for classifying FUO or IUO; (3) initial evaluation approaches; (4) a classification system for diagnoses; and (5) recommendations for judicious limitation of empiric therapies. Experts strongly disagreed with using 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography as part of the diagnostic criteria for FUO. There were mixed opinions about the importance of the temperature measurement site, the 3-week minimum illness criterion, the need for a standard definition of relapsing fevers, and the use of similar evaluation strategies for FUO and IUO. Conclusions These Delphi-generated consensus-based recommendations offer potential improvements compared with earlier definitions and a guide for clinical practice and future research.

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

Whole-body MRI is increasingly used in the evaluation of a range of oncological and non-oncological diseases in infants, children and adolescents. Technical innovation in MRI scanners, coils and sequences have enabled whole-body MRI to be performed more rapidly, offering large field-of-view imaging suitable for multifocal and multisystem disease processes in a clinically useful timeframe. Together with a lack of ionizing radiation, this makes whole-body MRI especially attractive in the pediatric population. Indications include lesion detection in cancer predisposition syndrome surveillance and in the workup of children with known malignancies, and diagnosis and monitoring of a host of infectious and non-infectious inflammatory conditions. Choosing which patients are most likely to benefit from this technology is crucial, but so is adjusting protocols to the patient and disease to optimize lesion detection. The focus of this review is on protocols and the elements impacting image acquisition in pediatric whole-body MRI. We consider the practical aspects, from scanner and coil selection to patient positioning, single-center generic and indication-specific protocols with technical parameters, motion reduction strategies and post-processing. When optimized, collectively these lead to better standardization of whole-body MRI, and when married to systematic analysis and interpretation, they can improve diagnostic accuracy.

Abstract Background Fever of unknown origin (FUO) investigations yield a substantial number of patients with infectious diseases. This systematic review and meta-analysis aimed to quantify more common FUO infectious diseases etiologies and to underscore geographic variation. Methods Four databases (PubMed, Embase, Scopus, and Web of Science) were searched for prospective studies reporting FUO rates among adult patients from 1 January 1997 to 31 March 2021. The pooled proportion for infectious diseases etiology was estimated using the random-effects meta-analysis model. Results Nineteen prospective studies were included with 2667 total cases. No studies were available for Africa or the Americas. Overall, 37.0% (95.0% confidence interval [CI], 30.0%–44.0%) of FUO patients had an infectious disease etiology. Infections were more likely from Southeastern Asia (pooled proportion, 0.49 [95% CI, .43–.55]) than from Europe (pooled proportion, 0.31 [95% CI, .22–.41]). Among specifically reported infectious diseases (n = 832), Mycobacterium tuberculosis complex predominated across all geographic regions (n = 285 [34.3%]), followed by brucellosis (n = 81 [9.7%]), endocarditis (n = 62 [7.5%]), abscesses (n = 61 [7.3%]), herpesvirus (eg, cytomegalovirus and Epstein-Barr virus) infections (n = 60 [7.2%]), pneumonia (n = 54 [6.5%]), urinary tract infections (n = 54 [6.5%]), and enteric fever (n = 40 [4.8%]). Conclusions FUO patients from Southeastern Asia were more likely to have an infectious diseases etiology when compared to other regions. The predominant factor for this finding appears to be differences in disease prevalence among various geographical locations or other factors such as access to timely care and diagnosis. Noting epidemiological disease factors in FUO investigations could improve diagnostic yields and clinical outcomes. Patients from Southeastern Asia with fever of unknown origin (FUO) are more likely than those from other geographical regions to have an infectious disease etiology. Noting epidemiological disease factors in FUO investigations could improve diagnostic yields and clinical outcomes.

Abstract Background Traditionally, 6-month courses of prednisolone are used to treat steroid-responsive meningitis-arteritis (SRMA), but this medication is associated with adverse effects that can lead to poor quality of life. Hypothesis/Objectives Resolution of clinical signs and rate of relapse of SRMA would not be significantly different between a 6-month prednisolone protocol and a 6-week protocol. Animals Forty-four hospital cases from multiple referral centers in the United Kingdom (2015-2019). Twenty of 44 were treated with the 6-month protocol and 24/44 with the 6-week protocol. Methods Prospective, randomized trial with 12-month follow-up. The same prednisolone protocol reinitiated in the event of relapse. Analysis of relapses with binary logistic and Poisson regression modeling. Results All cases responded to their treatment protocol. Relapses occurred in 6/20 (30%) of the 6-month protocol and 9/24 (38%) of the 6-week protocol. There was no statistical difference in the incidence risk of at least 1 relapse between the 2 groups (odds ratio = 1.40; 95% confidence interval [CI], 0.40-4.96, P = 0.60). Among the 15 dogs that relapsed, 10/15 (67%) relapsed once, 3/15 (20%) relapsed twice, and 2/15 (13%) relapsed 3 times. No statistical difference was detected in the incidence rate ratio (IRR) of total relapse events between the 2 groups (IRR = 1.46; 95% CI, 0.61-3.48; P = 0.40). Conclusions and Clinical Importance “Short” 6-week prednisolone protocols could be used to treat SRMA, thereby presumably reducing the duration and severity of prednisolone's adverse effects.

Background Despite advancements in diagnostic technology, pyrexia of unknown origin (PUO) remains a clinical concern. Insufficient information is available regarding the cost of care for the management of PUO in the South Asian Region. Methods We retrospectively analyzed data of patients with PUO from a tertiary care hospital in Sri Lanka to determine the clinical course of PUO and the burden of the cost incurred in the treatment of PUO patients. Non-parametric tests were used for statistical calculations. Results A total of 100 patients with PUO were selected for the present study. The majority were males (n = 55; 55.0%). The mean ages of male and female patients were 49.65 (SD: 15.55) and 46.87 (SD: 16.19) years, respectively. In the majority, a final diagnosis had been made (n = 65; 65%). The mean number of days of hospital stay was 15.16 (SD; 7.81). The mean of the total number of fever days among PUO patients was 44.47 (SD: 37.66). Out of 65 patients whose aetiology was determined, the majority were diagnosed with an infection (n = 47; 72.31%) followed by non-infectious inflammatory disease (n = 13; 20.0%) and malignancies (n = 5; 7.7%). Extrapulmonary tuberculosis was the most common infection detected (n = 15; 31.9%). Antibiotics had been prescribed for the majority of the PUO patients (n = 90; 90%). The mean direct cost of care per PUO patient was USD 467.79 (SD: 202.81). The mean costs of medications & equipment and, investigations per PUO patient were USD 45.33 (SD: 40.13) and USD 230.26 (SD: 114.68) respectively. The cost of investigations made up 49.31% of the direct cost of care per patient. Conclusion Infections, mainly extrapulmonary tuberculosis was the most common cause of PUO while a third of patients remained undiagnosed despite a lengthy hospital stay. PUO leads to high antibiotic usage, indicating the need for proper guidelines for the management of PUO patients in Sri Lanka. The mean direct cost of care per PUO patient was USD 467.79. The cost of investigations contributed mostly to the direct cost of care for the management of PUO patients.

Abstract Background Diagnostic outcomes for fever of unknown origin (FUO) remain with notable numbers of undiagnosed cases. A recent systemic review and meta-analysis of studies reported geographic variation in FUO-related infectious diseases. Whether geography influences types of FUO noninfectious diagnoses deserves examination. Methods We systematically searched Medline (PubMed), Embase, Scopus, and Web of Science databases using medical subject headings published from January 1, 1997 to March 31, 2021. Prospective clinical studies investigating participants meeting adult FUO defining criteria were selected if they assessed final diagnoses. Meta-analyses were based on the random-effects model according to World Health Organization (WHO) geographical regions. Results Nineteen studies with significant heterogeneity were analyzed, totaling 2667 participants. Noninfectious inflammatory disorders had a pooled estimate at 20.0% (95% confidence interval [CI], 17.0%–23.0%). Undiagnosed illness had a pooled estimate of 20.0% (95% CI, 14.0%–26.0%). The pooled estimate for cancer was 15.0% (95% CI, 12.0%–18.0%). Miscellaneous conditions had a pooled estimate of 6.0% (95% CI, 4.0%–8.0%). Noninfectious inflammatory disorders and miscellaneous conditions were most prevalent in the Western Pacific region with a 27.0% pooled estimate (95% CI, 20.0%–34.0%) and 9.0% (95% CI, 7.0%–11.0%), respectively. The highest pooled estimated for cancer was in the Eastern Mediterranean region at 25.0% (95% CI, 18.0%–32.0%). Adult-onset Still’s disease (114 [58.5%]), systemic lupus (52 [26.7%]), and giant-cell arteritis (40 [68.9%]) predominated among the noninfectious inflammatory group. Lymphoma (164 [70.1%]) was the most common diagnosis in the cancer group. Conclusions In this systematic review and meta-analysis, noninfectious disease diagnostic outcomes varied among WHO-defined geographies. Evaluations for FUO should include local variations in disease prevalence. Geographical location influenced adult FUO syndrome noninfectious diseases diagnoses. Noninfectious inflammatory disorders were most prevalent in the Western Pacific region. The highest pooled estimate for cancer was in the Eastern Mediterranean region.

The syndrome of pyrexia of unknown origin (PUO) was first defined in 1961 but remains a clinical challenge for many physicians. Different subgroups with PUO have been suggested, each requiring different investigative strategies: classical, nosocomial, neutropenic and HIV-related. This could be expanded to include the elderly as a fifth group. The causes are broadly divided into four groups: infective, inflammatory, neoplastic and miscellaneous. Increasing early use of positron emission tomography–computed tomography (PET-CT) and the development of new molecular and serological tests for infection have improved diagnostic capability, but up to 50% of patients still have no cause found despite adequate investigations. Reassuringly, the cohort of undiagnosed patients has a good prognosis. In this article we review the possible aetiologies of PUO and present a systematic clinical approach to investigation and management of patients, recommending potential second-line investigations when the aetiology is unclear.

Abstract Background Classifying fever of unknown origin (FUO) into categorical etiologies (ie, infections, noninfectious inflammatory, oncologic, miscellaneous, and undiagnosed disorders) remains unstandardized and subject to discrepancies. As some disease classifications change, a systematic review of studies would help physicians anticipate the frequency of illness types they may encounter that could influence care. Methods We systematically reviewed prospective FUO studies published across the Medline (PubMed), Embase, Scopus, and Web of Science databases from January 1, 1997, to July 31, 2022. We performed a meta-analysis to estimate associated pooled proportions between the investigator-determined choice of disease category and those determined by the International Classification of Diseases, 10th edition (ICD-10), methodology. Results The proportion of patients with a difference between the investigator and ICD-10-adjusted noninfectious inflammatory disorder category was 1.2% (95% CI, 0.005–0.021; P < .001), and the proportion was similar for the miscellaneous category at 1.5% (95% CI, 0.007–0.025; P < .001). The miscellaneous and noninfectious inflammatory disorders categories demonstrated significant across-study heterogeneity in the proportions of patients changing categories, with 52.7% (P = .007) and 51.0% (P = .010) I2, respectively. Conclusions Adjusting FUO-associated diagnoses by ICD-10 methodology was associated with a statistically significant risk of over- or underestimation of disease category frequency approximation when using a 5 FUO category system. An FUO diagnostic classification system that better reflects mechanistic understanding would assist future research and enhance comparability across heterogenous populations and different geographic regions. We propose an updated FUO classification scheme that streamlines categorizations, aligns with the current understanding of disease mechanisms, and should facilitate empirical decisions, if necessary.