BACKGROUND: Criteria classifying fever of unknown origin (FUO) patients remains subject to discrepancies. A minimal standardized set of investigative tests serves as the foundation for the qualitative criteria, whereas quantitative incorporates the length of evaluation (7 or 3 days). A systematic review of studies would help physicians anticipate the frequency of illness types that could influence management.
METHODS: Prospective studies published in Medline (PubMed), Embase, Scopus, and Web of Science databases from January 1, 1997, to July 31, 2022, were included. A meta-analysis estimated associated pooled proportions between these criteria and diagnostic outcomes adjusted to the International Classification of Diseases, 10th edition (ICD-10) definitions.
RESULTS: Five qualitative studies corresponded to an increase of 15.3% (95% CI: 2.3-28.3%, p=0.021) in undiagnosed FUO proportions compared to eleven quantitative studies. Quantitative studies had 19.7% (95% CI: 6.0-33.4%, p=0.005) more in adjusted infectious disease proportions than qualitative studies. No significant differences in proportions between FUO defining criteria were noted for adjusted noninfectious inflammatory disorders (p=0.318), oncology (p=0.901), non-inflammatory miscellaneous disorders (p=0.321), diagnostic evaluation process, gross national income (GNI), or World Health Organization (WHO) geographic region.
CONCLUSIONS: Use of either qualitative or quantitative FUO criteria was associated with a statistically significant risk of over- or under-estimating infectious diseases and undiagnosed illnesses when using an ICD-10 adjusted FUO five-category system. Clinicians should anticipate differences depending on which criteria are used. While further research is warranted, qualitative criteria provide the best framework for study comparisons.

Metagenomic Next-Generation Sequencing (mNGS) holds promise in diagnosing fever of unknown origin (FUO) by detecting diverse pathogens. We systematically reviewed the literature to evaluate mNGS\'s accuracy, clinical efficacy, and limitations in FUO diagnosis. Nine studies revealed mNGS\'s positivity rate ranging from 66.7% to 93.5% for bacterial bloodstream infections and systemic infections. Meta-analysis of three studies involving 857 patients, including 354 with FUO, showed a sensitivity of 0.91 (95% CI: 0.87-0.93) and specificity of 0.64 (95% CI: 0.58-0.70). Despite lower specificity, mNGS demonstrated a higher Diagnostic Odds Ratio (DOR) of 17.0 (95% CI: 4.5-63.4) compared to conventional microbiological tests (CMTs) at 4.7 (95% CI: 2.9-7.6). While mNGS offers high sensitivity but low specificity in identifying causative pathogens for FUO, its superior DOR suggests potential for more accurate diagnoses and targeted interventions. Further research is warranted to optimize its clinical application in FUO management.

BACKGROUND: Nocardia is an ubiquitous soil organism. As an opportunistic pathogen, inhalation and skin inoculation are the most common routes of infection. Lungs and skin are the most frequent sites of nocardiosis. Testis is a highly unusual location for nocardiosis.
METHODS: We report the case of an immunocompromised 75-year-old-man admitted for fever of unknown origin. He presented with skin lesions after gardening and was first suspected of Mediterranean spotted fever, but he did not respond to doxycycline. Then, physical examination revealed new left scrotal swelling that was compatible with a diagnosis of epididymo-orchitis. The patient\'s condition did not improve despite empirical antibiotic treatment with the onset of necrotic scrotal abscesses requiring surgery. Nocardia brasiliensis yielded from the removed testis culture. High-dose trimethoprim-sulfamethoxazole and ceftriaxone were started. Multiple micro-abscesses were found in the brain and spinal cord on imaging studies. After 6 weeks of dual antibiotic therapy for disseminated nocardiosis, slight regression of the brain abscesses was observed. The patient was discharged after a 6-month course of antibiotics and remained relapse-free at that time of writing these lines. Trimethoprim-sulfamethoxazole alone is meant to be pursued for 6 months thereafter. We undertook a literature review on previously reported cases of genitourinary and urological nocardiosis; to date, only 36 cases have been published with predominately involvement of kidney, prostate and testis.
CONCLUSIONS: To the best of our knowledge, this is the first case of Nocardia brasiliensis simultaneously infecting skin, testis, brain and spinal cord in an immunocompromised patient. Knowledge on uncommon forms of nocardiosis remains scarce. This case report highlights the difficulty of diagnosing atypical nocardiosis and the importance of prompt bacteriological sampling in case of empirical antibiotics failure.

BACKGROUND: Patients with inflammation of unknown origin (IUO) and fever of unknown origin (FUO) are commonly considered a single population. Differences in underlying causes between both groups may steer the diagnostic work-up.
METHODS: PubMed, Embase, Web of Science, and ClinicalTrials.gov were searched from July 2009 through December 2023. Studies including both FUO and IUO patients with a sample size of ≥20 were considered. The primary outcome was the difference in the rate of patients affected by predefined diagnostic categories according to meeting FUO or IUO criteria. Data were pooled using random-effects models.
RESULTS: A total of 8 studies met criteria for inclusion, with a total of 1452 patients (466 with IUO and 986 with FUO). The median rate of IUO patients among the included studies was 32 % (range 25-39 %). Patients with IUO had a lower likelihood of infection (OR 0.59 [95 % CI; 0.36-0.95]; I2 0 %). There were no significant differences in the rate of noninfectious inflammatory disorders, malignancies, miscellaneous disorders, or remaining undiagnosed. Comparison of diagnostic subgroups revealed that IUO patients were less likely to have systemic autoinflammatory disorders (OR 0.17 [95 % CI, 0.05-0.58]; I2 42 %) and more likely to have vasculitis (OR 2.04 [95 % CI, 1.23-3.38]; I2 21 %) and rheumatoid arthritis or spondylarthritis (OR 3.52 [95 % CI, 1.16-10.69]; I2 0 %).
CONCLUSIONS: Based on our findings, there is little reason to assume that FUO and IUO patients would benefit from a different initial diagnostic approach.

Human brucellosis, one of the most common zoonoses worldwide, is rare in Japan. Brucella canis is the specific pathogen of human brucellosis carried by dogs. According to an epidemiological study of B. canis infection in Japan, B. canis is the specific pathogen of human brucellosis in dogs. We herein report a rare case of meningoencephalomyelitis caused by B. canis in a 68-year-old Japanese man. Neurobrucellosis was diagnosed based on a serum tube agglutination test and abnormal cerebrospinal fluid findings. The patient was started on targeted treatment with a combination of doxycycline and streptomycin. Although extremely rare, neurobrucellosis should be considered in patients with a fever of unknown origin and unexplained neurological symptoms.

UNASSIGNED: Fever of unknown origin (FUO) in children poses a complex challenge for doctors. It involves a broad spectrum of potential diagnoses, with infectious diseases being the predominant culprits, followed by connective tissue disorders and malignancies.
METHODS: A 4-year-old boy with a prior diagnosis of a congenital bicuspid aortic valve was admitted to our hospital after experiencing two months of intermittent high-grade fever, severe nighttime headaches, and episodes of nausea and vomiting. His condition deteriorated rapidly with a drop in hemoglobin, elevated inflammatory markers, and the discovery of a large intracerebral hematoma. Further evaluation revealed infective endocarditis and a ruptured cerebral mycotic aneurysm associated with the bicuspid aortic valve infection. The aneurysm was successfully treated through cerebral endovascular catheterization, and the patient received six weeks of intravenous antibiotics. Cardiac surgery for valve repair was planned for a later date.
UNASSIGNED: Among the infectious causes, infective endocarditis (IE) is a notable contributor, accounting for 1-5 % of all FUO cases. IE can lead to severe complications, with a small fraction of patients experiencing neurological issues such as stroke, encephalopathy, or the development of cerebral mycotic aneurysms.
CONCLUSIONS: The presented case serves as a stark reminder that FUO can be caused by serious underlying conditions, such as infective endocarditis. The rapid progression from fever and neurological symptoms to a ruptured cerebral mycotic aneurysm highlights the potentially life-threatening nature of these cases.

BACKGROUND: Antisynthetase syndrome is an inflammatory myopathy that is characterized by the presence of anti-aminoacyl-tRNA synthetase antibodies. Only 30% of those who suffer from the disease can be identified. We present three Hispanic cases of antisynthetase syndrome with unusual clinical pictures were extended myositis panel results enable disease diagnosis and treatment.
METHODS: A 57-year-old Hispanic/Latino female with an erythematous scaly plaque, unresolved fever and non-immune haemolytic anaemia in whom inpatient work-up for fever of unknown origin was positive for anti-PL12 positive myositis extended panel. A 72-year-old Hispanic/Latino male with amyopathic weakness syndrome and mechanic hands in whom impatient work-up was relevant for proximal muscle uptake and anti-PM75 and AntiPL-12 myositis extended panel. And a 67-year-old Hispanic/Latino male with progressive interstitial lung disease and unresolved fever ended in myositis extended panel positive for antiPL-7. After systemic immunosuppressor treatment, patients had favourable clinical and paraclinical responses during outpatient follow-up.
CONCLUSIONS: The high variability of the antisynthetase syndrome in these cases demonstrates the importance of identification through an expanded panel and highlights the probability that this is a variable disease and that we need to include emerging molecular tests to promote the timely treatment of patients.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

A 60-year-old Chinese female patient was admitted to the hospital with complaint of intermittent fever for more than seven months. The main clinical manifestations were acute kidney injury and nephrotic syndrome which developed into a hemophagocytic syndrome. The symptoms did not improve with antibiotics. Moreover, prednisone could only reduce the fever. Finally, a kidney biopsy showed many CD20-positive cells in the glomerulus and some in the peritubular capillaries. This led to a diagnosis of renal intravascular large B-cell lymphoma.

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