UNASSIGNED: Fever of unknown origin is quite common in everyday clinical practice, and the approach is challenging. Prolonged fever as the sole manifestation of craniopharyngioma has been rarely reported in literature.
UNASSIGNED: Herein, we report a case of adamantinomatous craniopharyngioma presented as fever of unknown origin in a 51-year-old woman, initially misdiagnosed as atypical subacute thyroiditis.
UNASSIGNED: During the work up, the patient complained about bitemporal hemianopsia. Thus, she underwent a pituitary Magnetic Resonance Imaging, which revealed a mixed mass originating from the pituitary stalk and compressing the optic chiasm. The mass was surgically excised, and the histology confirmed the diagnosis of adamantinomatous craniopharyngioma. The patient remained afebrile post-surgery. We hypothesize that the craniopharyngioma caused an abnormality of thermoregulatory mechanisms due to infiltration of the hypothalamus.

Fever of unknown origin (FUO) remains a formidable diagnostic challenge in the field of medicine. Numerous studies suggest an association between FUO and genetic factors, including chromosomal abnormalities. Here, we report a female patient with a 4.5 Mb Xp microdeletion, who presented with recurrent FUO, bacteremia, colitis, and hematochezia. To elucidate the underlying pathogenic mechanism, we employed a comprehensive approach involving single cell RNA sequencing, T cell receptor sequencing, and flow cytometry to evaluate CD4 T cells. Analysis of peripheral blood mononuclear cells revealed augmented Th1, Th2, and Th17 cell populations, and elevated levels of proinflammatory cytokines in serum. Notably, the patient exhibited impaired Treg cell function, possibly related to deletion of genes encoding FOPX3 and WAS. Single cell analysis revealed specific expansion of cytotoxic CD4 T lymphocytes, characterized by upregulation of various signature genes associated with cytotoxicity. Moreover, interferon-stimulated genes were upregulated in the CD4 T effector memory cluster. Further genetic analysis confirmed maternal inheritance of the Xp microdeletion. The patient and her mother exhibited X chromosome-skewed inactivation, a potential protective mechanism against extensive X chromosome deletions; however, the mother exhibited complete skewing and the patient exhibited incomplete skewing (85:15), which may have contributed to emergence of immunological symptoms. In summary, this case report describes an exceptional instance of FUO stemming from an incompletely inactivated X chromosome microdeletion, thereby increasing our understanding of the genetics underpinning FUO.

UNASSIGNED: Fever of unknown origin (FUO) has long been a cause for concern among clinicians, and its spectrum has evolved with progress in medicine. This study aimed to investigate the distribution of causes of FUO in China between 2013 and 2022 to facilitate the clinical understanding of the etiology of FUO.
UNASSIGNED: Case series of FUO in China published between 2013 and 2022 were retrieved from PubMed, Wanfang Data, and CNKI databases and retrospectively analyzed. The rates of different causes of FUO were calculated, and these data were compared with previously published distributions of causes of FUO in China.
UNASSIGNED: The causes of FUO with the highest rates from the 51 identified case series (n = 19,874) were infectious, autoimmune, and neoplastic diseases (59.6%, 14.3%, and 7.9%, respectively). A comparison of a subset (43 case series subdivided by disease category, n = 16,278) with previously reported data revealed an increased rate of FUO attributed to infectious diseases in the past decade, with a significantly higher rate attributed to bloodstream infections (10.0% vs. 4.8%) and a significantly lower rate attributed to tuberculosis (9.3% vs. 28.4%), compared with the rates from the previous period. In contrast, the rates of FUO attributed to both autoimmune and neoplastic diseases decreased, with significantly decreased rates attributed to adult-onset Still\'s disease among autoimmune diseases (4.6% vs. 8.5%) and lung cancer among neoplastic diseases (0.6% vs. 1.6%).
UNASSIGNED: Despite an overall increase in the rate attributed to infectious diseases, that attributed to tuberculosis has decreased. The rates attributed to both autoimmune and neoplastic diseases have also decreased.

Febrile neutropenia (FN) is a complication in approximately 90% of autologous stem cell transplant (SCT) patients. Guidelines support early broad-spectrum antibiotics (BSA) to prevent morbidity and mortality. However, in patients who are clinically stable and deemed to have a fever of unknown origin, the optimal duration of BSA is unknown. Accumulating evidence suggests that de-escalation of BSA in select patients may decrease duration of BSA exposure without compromising clinical outcomes such as infection, recurrent fever, and readmission. With this, a de-escalation protocol was implemented at Vanderbilt University Medical Center (VUMC) to identify autologous SCT patients who may benefit from early de-escalation of BSA. The objectives of this study were to analyze the impact of early empiric antibiotic de-escalation on the duration of BSA as well as its impact on the incidence of recurrent fever and documented infection in autologous SCT patients. This was a single-center, retrospective study evaluating patients older than 18 years of age who underwent autologous SCT and experienced an episode of FN from January 2018 to December 2022 at VUMC (N = 195). The protocol was initiated on January 1, 2020, to de-escalate BSA back to prophylaxis in stable neutropenic patients determined to have a fever of unknown origin. The primary outcome was the number of BSA days within 30 days. Secondary clinical outcomes included recurrent fever, documented infection, readmission, 30-day mortality, and 90-day non-relapsed mortality (NRM). Outcomes were compared across pre- and postprotocol groups with a Wilcoxon rank sum test, Pearson chi-square test, or regression analysis as appropriate. The median BSA duration was 4.7 and 2.7 days in the pre- and postprotocol groups, respectively (P < .001). Recurrent fever (14.2% versus 16.0%, P = .726), documented infection (1.7% versus 6.7%, P = .068), and readmission (13.3% versus 22.7%, P = .091) within 30 days were not significantly different between the two groups. Neither 30-day mortality (0.8% versus 1.3%, P = .736) nor 90-day NRM (0.8% versus 1.3%, P = .736) differed. The implementation of an early de-escalation protocol for autologous SCT patients who develop FN was associated with a reduction in duration of BSA compared to the preprotocol group without a significant difference in readmission, recurrent fevers, and documented infections. This study adds to existing evidence that early de-escalation of BSA in FN patients with a fever of unknown origin who are afebrile and clinically stable is safe and reduces unnecessary antibiotic use.

Diagnosing neoplastic fever requires excluding identifiable causes, making it a diagnostic challenge. Fever as a primary manifestation of pancreatic adenocarcinoma is uncommon with few cases reported in the literature. Here we present an unusual case of metastatic pancreatic adenocarcinoma primarily manifesting as pyrexia of unknown origin. A 63-year-old Sri Lankan male, a non-smoker who was diagnosed with diabetes, hypertension and dyslipidaemia presented with a history of fever, anorexia and weight loss for 2 months. Despite the completion of treatment for positive serology for paratyphi, his symptoms and inflammatory markers remained elevated while the rest of the infectious screening was negative. On further evaluation, the patient was found to have a hypodense distal pancreas with ring-enhancing multiple liver lesions on imaging. Histology confirmed pancreatic adenocarcinoma with liver metastasis. Atypical liver metastases may present with evidence of ring enhancement in computed tomography imaging; thus, the biopsy is mandatory for diagnosis and decision-making. Usually, tumours of the pancreatic tail are resectable but if they are associated with liver metastatic disease, surgical resection is not recommended because it is not potentially curative. Therefore, in the context of metastatic pancreatic adenocarcinoma, palliative chemotherapy and pharmacological management of fever are required.

A 53-year-old otherwise healthy man was referred to our hospital with a fever of unknown origin, headache, and arthralgia. Four days earlier, he had a fever with chills. Treatment with antibiotics and acetaminophen proved ineffective, with the patient subsequently developing headache and joint pain. Blood analysis revealed elevated inflammatory markers, liver impairment, and severe thrombocytopenia (platelet count, 19,000/μL). Subsequent tests revealed elevated levels of anti-cytomegalovirus IgM and IgG. Based on these findings, the patient was diagnosed with severe thrombocytopenia associated with cytomegalovirus infection. Platelet counts increased spontaneously without antiviral therapy. Forty-five days after the initial visit, the symptoms improved, and blood tests revealed resolution of the inflammatory findings, with the platelet count recovering to 155,000/μL. Although the disease may resolve spontaneously, cytomegalovirus infection should be considered as a differential diagnosis in case of severe thrombocytopenia in immunocompetent adults.

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: Suspected infection or inflammation of unknown origin in in-patients remains challenging. Literature on [18F]FDG-PET/CT is abundant in classic fever of unknown origin (FUO), but evidence is complex and may not always reflect clinical reality. This study explores the application of [18F]FDG-PET/CT in a diverse clinical population of in-patients with suspected infection not defined by stringent FUO-criteria.
METHODS: Retrospective chart review of consecutive in-patients who underwent [18F]FDG-PET/CT in the workup of suspected infection or inflammation from 1 July 2022 to 31 December 2022 was conducted. We evaluated indications, diagnostic yield, and clinical impact of [18F]FDG-PET/CT, and compared the findings of [18F]FDG-PET/CT and stand-alone CT. Univariate logistic regression assessed associations between [18F]FDG-PET/CT outcome and clinical parameters. Receiver operating characteristic curve (ROC) analysis evaluated diagnostic performance.
RESULTS: 77 patients met the inclusion criteria. [18F]FDG-PET/CT established a diagnosis in 35% of cases, ruled out focal infection in 26%, and thus was helpful in 61% of patients. It prompted 72 additional examinations resulting in seven incidental diagnoses, including two cancers. Antibiotic treatment was changed in 26% of cases. Regression analysis found white blood cell counts (WBC) associated with true positive outcomes. [18F]FDG-PET/CT was compared to stand-alone CT findings, and was concordant in 69% of cases.
CONCLUSIONS: Results were comparable to findings in more classic FUO. [18F]FDG-PET/CT was clinically helpful in 61% of cases but also prompted many additional examinations with relatively few clinically important findings. WBC count was a predictor of true positive outcome. CT and [18F]FDG-PET/CT were discordant in 31%, of cases, especially in cases of endocarditis and spondylodiscitis.

BACKGROUND: Fever of unknown origin (FUO) is a diagnostic challenge with highly heterogeneous causes. Its etiology can change according to the studied regions, and the chance of reaching a diagnosis depends on available resources. The aim of this study is to describe the clinical characteristics, etiology and the usefulness of diagnostic aids in cases of FUO managed over 12 years in a Colombian reference center.
METHODS: Single-institution retrospective case series. All cases of FUO between 2006 and 2017 were identified with the help of an electronic medical record search software. Cases of adults with fever for more than three weeks who remained undiagnosed after three days of hospitalization are described.
RESULTS: Of 1,009 cases evaluated, 112 cases met the inclusion criteria (median age 43 years, 66% men). The etiologies identified were infectious (31.2%), inflammatory (20.5%), neoplastic (14.3%), and miscellaneous (2.7%) diseases. 31.2% remained without etiological diagnosis. The most frequent conditions were tuberculosis (17%), Hodgkin\'s lymphoma (7.1%), systemic lupus erythematosus (6.3%), disseminated histoplasmosis, and adult Still\'s disease. Contrast tomography and biopsies were the studies that most frequently supported or confirmed the final diagnosis.
CONCLUSIONS: This series of contemporary Latin American cases suggests that the categories of FUO etiologies are similar to those reported in studies from developed countries, with tuberculosis being the most frequent cause in our setting. Our results highlight the importance of tomography-guided invasive studies in the diagnostic approach to FUO.