[The 506th case: fever of unknown origin, negative PET-CT and hemoperitoneum].

A 48-year-old male was admitted to Peking Union Medical College Hospital presented with intermittent fever for two years. The maximum body temperature was 39 ℃, and could spontaneously relieve. The efficacy of antibacterial treatment was poor. He had no other symptoms and positive signs. He had a significant weight loss, and the serum lactate dehydrogenase increased significantly. It was highly alert to be lymphoma, but bone marrow smear and pathology, and PET-CT had not shown obvious abnormalities. Considering high inflammatory indicators, increased ferritin and large spleen, the patient had high inflammatory status, and was treated with methylprednisolone. Then the patient's body temperature was normal, but the platelet decreased to 33×109/L. During hospitalization, he had suddenly hemoperitoneum and hemorrhagic shock. He was found spontaneous spleen rupture without obvious triggers, and underwent emergency splenectomy. The pathological diagnosis of spleen was diffuse large B-cell lymphoma.

Safety of empirical antibiotic therapy discontinuing for fever of unknown origin during high-risk neutropenia in children.

BACKGROUND: ECIL-2021 recommends discontinuing empirical antibiotic therapy (EAT) in febrile-neutropenic children after 72 h of treatment and at least 24-48 h of apyrexia in the case of fever of unknown origin (FUO). These guidelines are rarely applied to high-risk children's neutropenia. MATERIAL AND METHODS: We retrospectively included all consecutive FUO episodes occurring during profound neutropenia ≥ 10 days in children in our institution. We evaluated the safety of EAT discontinuation in patients for whom the ECIL guidelines were followed compared to those for whom they didn't. We used a combined criterion of mortality and intensive care unit admission at 30 days. We identified risk factors for recurrent fever after EAT discontinuation. RESULTS: Fifty-one FUO episodes occurred in 37 patients. EAT discontinuation followed ECIL guidelines in 19 (37 %) episodes. No deaths and-or transfers in ICU occurred in the ECIL group. The duration of EAT was shorter by nine days in the group following ECIL guidelines (p < 0.001). We observed 14 (27 %) episodes of recurrent fever. Mucositis was significantly associated with recurrent fever (p < 0.01). CONCLUSION: EAT discontinuation seems feasible and safe in FUO during prolonged febrile neutropenia in children. However, mucosal lesions should prompt thorough surveillance due to the risk of recurrent fever.

Performance of Febrile Infant Algorithms by Duration of Fever.

OBJECTIVES: To analyze the performance of commonly used blood tests in febrile infants ≤90 days of age to identify patients at low risk for invasive bacterial infection (bacterial pathogen in blood or cerebrospinal fluid) by duration of fever. METHODS: We conducted a secondary analysis of a prospective single-center registry that includes all consecutive infants ≤90 days of age with fever without a source evaluated at 1 pediatric emergency department between 2008 and 2021. We defined 3 groups based on caregiver-reported hours of fever (<2, 2-12, and ≥12) and analyzed the performance of the biomarkers and Pediatric Emergency Care Applied Research Network, American Academy of Pediatrics, and Step-by-Step clinical decision rules. RESULTS: We included 2411 infants; 76 (3.0%) were diagnosed with an invasive bacterial infection. The median duration of fever was 4 (interquartile range, 2-12) hours, with 633 (26.3%) patients with fever of <2 hours. The area under the curve was significantly lower in patients with <2 hours for absolute neutrophil count (0.562 vs 0.609 and 0.728) and C-reactive protein (0.568 vs 0.760 and 0.812), but not for procalcitonin (0.749 vs 0.780 and 0.773). Among well-appearing infants older than 21 days and negative urine dipstick with <2 hours of fever, procalcitonin ≥0.14 ng/mL showed a better sensitivity (100% with specificity 53.8%) than that of the combination of biomarkers of Step-by-Step (50.0% and 82.2%), and of the American Academy of Pediatrics and Pediatric Emergency Care Applied Research Network rules (83.3% and 58.3%), respectively. CONCLUSIONS: The performance of blood biomarkers, except for procalcitonin, in febrile young infants is lower in fever of very short duration, decreasing the accuracy of the clinical decision rules.

[Workplace-associated fever]. / Arbeitsplatzassoziiertes Fieber oder wenn es doch das Zebra ist .

INTRODUCTION: Febrile conditions often have an infectious etiology. However, there are also fevers associated with occupational exposures. A detailed occupational history can hold the key to the diagnosis. In the case of exposure to organic dusts, the development of hypersensitivity pneumonitis (HP) is possible. Thus, HP should be considered in the presence of interstitial lung disease of unclear etiology. Failure to recognize this can have dramatic consequences and, in extreme cases, lead to lung transplantation. Differentially, organic dust toxic syndrome (ODTS) must be considered. The syndrome of metal fume fever provoked by inhalation of inorganic substances is usually benign and self-limiting. The disease manifests with fever, cough, and flu-like sensations.

Lesson of the month: Large vessel vasculitis: A rare cause of transaminitis.

We present the case of a 73-year-old male with pyrexia of unknown origin (PUO). He was a returned traveller from Southern Africa and underwent extensive investigation to rule out an infective cause. This was mostly unrevealing but there was a notable transaminitis (ALT predominant) with normal bilirubin level. He showed no serological or clinical improvement despite antibiotic treatment. Subsequent CT-PET showed high mural uptake in the thoracic and abdominal aorta and its major branches, confirming the diagnosis of Large Vessel Vasculitis (LVV). This case highlights the importance of considering LVV in patients with PUO and with transaminitis.

Unraveling the mystery of fever of unknown origin: a remarkable journey towards the diagnosis of peripheral T-cell lymphoma-T follicular helper type: A rare case report.

INTRODUCTION: Fever of unknown origin (FUO) remains one of the most challenging clinical conditions. It demands an exhaustive diagnostic approach, considering its varied etiologies spanning infectious, autoimmune, inflammatory, and malignant causes. PATIENT CONCERNS: This report shows the journey of diagnosing a 28-year-old male who presented with persistent fever and lower-extremity weakness over 9 months. Despite seeking care at multiple hospitals, a definitive diagnosis remained elusive. DIAGNOSIS: The patient underwent a series of evaluations in various specialties, including gastroenterology, infectious diseases, rheumatology, hematology, and cardiology. Multiple tests and treatments were administered, including antiviral therapy for hepatitis B and antibiotics for suspected infections. INTERVENTIONS: After an initial misdiagnosis and unsuccessful treatments, a positron emission tomography-computed tomography scan and lymph node biopsy ultimately led to the diagnosis of peripheral T-cell lymphoma-T follicular helper type (PTCL-TFH) lymphoma. The patient was referred to the hematology clinic and initiated on CHOEP (cyclophosphamide, vincristine, etoposide, and prednisone) chemotherapy. OUTCOMES: The patient showed a positive response to CHOEP therapy, as indicated by a posttreatment positron emission tomography-computed tomography scan. He reported a significant improvement in his quality of life. Additional rounds of the same regimen were planned to further manage the lymphoma. CONCLUSION: This case emphasizes the importance of a comprehensive and persistent diagnostic approach in managing FUO. Initially, the focus on infectious causes led to extensive treatments, but the disease's progression and complications shifted attention to other specialties. The eventual diagnosis of PTCL-TFH lymphoma highlights the significance of advanced imaging techniques and multidisciplinary collaboration in uncovering elusive diagnoses. Thorough surveillance, timely reassessments, and repeated testing can uncover definitive changes critical for diagnosis. PTCL-TFH lymphoma, although rare, should be considered in the differential diagnosis of FUO, especially when initial evaluations are inconclusive.

No Impact of Dietary Restrictions on the Risk for Infection in Pediatric Patients With Cancer: A Monocenter Analysis.

PURPOSE: Prophylactic anti-infective strategies are used in patients with cancer to decrease the risk for infection. Dietary restrictions do not allow raw vegetables and fresh fruits to limit the introduction of potentially harmful pathogens in the gastrointestinal tract, but the efficacy is unclear. PATIENTS AND METHODS: In this study analyzing the impact of the dietary restrictions on infectious complications, all children treated between April 2014 and March 2018 for ALL and AML or non-Hodgkin lymphoma (NHL) were included. Dietary restrictions were standard until March 2016, but were stopped in April 2016. Patients with dietary restrictions (treated April 2014-March 2016) and patients not advised for dietary restrictions (treated April 2016-March 2018) were compared regarding infectious complications, including bloodstream infection, pneumonia, diarrhea, and fever of unknown origin (FUO). RESULTS: Eighty-six patients (25 female; 62 ALL; nine AML, 15 NHL) experienced 223 infections. The 46 patients with dietary restrictions and the 40 patients without food restrictions did not significantly differ regarding the number of infections per patient, bloodstream infections, pneumonia, diarrhea, FUO, admission to intensive care, and death. CONCLUSION: Our data suggest that dietary restrictions do not affect the risk for infectious complications. Therefore, the indication of dietary restrictions should be reconsidered in pediatric patients with cancer.

Significance of F-18 FDG PET/MRI in the search for the etiology of inflammation of unclear origin and fever of unknown origin.

PURPOSE: To evaluate the contribution of F-18 FDG-PET/MRI in the search for the etiology of the inflammation of unknown origin (IUO) and fever of unknown origin (FUO). MATERIAL AND METHODS: The study included 104 patients who underwent F-18 FDG-PET/MRI for IUO or FUO. The sensitivity, specificity, predictive values of the PET/MRI findings in relation to the final diagnosis of IUO/FUO were evaluated. A five-point Likert scale was used to semiquantitatively assess the probability of the cause of IUO/FUO based on PET/MRI finding. Furthermore, clinical (fever, arthralgia, weight loss, night sweats, age) and laboratory (C-reactive protein, leukocytes) parameters were monitored and compared with the true positivity rate of PET/MRI. RESULTS: In patients with definitively identified etiology of FUO and IUO, FDG-PET/MRI achieved a sensitivity of 96 %, specificity of 82 %, and positive and negative predictive values of 92 and 90 %. The cause of the IUO was determined in 71 patients (68.3 %). In 33 (31.7 %) patients, the etiology of IUO/FUO remained unknown, while in 25 (75.8 %) of them the symptoms resolved spontaneously and in 8 (24.2 %) patients they persisted without explanation even after 12 months of the follow-up. The most significant parameter in relation to subsequent PET/MRI finding was increased level of CRP, which was present in 96 % of true positive PET/MRI and normal CRP level was present in 56 % of true negative PET/MRI. CONCLUSION: Based on this study, FDG-PET/MRI is a suitable alternative for the investigation of IUO/FUO, this imaging technique has a very high sensitivity and negative predictive value.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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 3 years 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 90 days 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. CONCLUSIONS: 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.

Predictive model for diagnostic yield of bone marrow examination in patients with HIV infection having fever of unknown origin.

OBJECTIVE: Bone marrow examination is valuable for identifying the cause of fever of unknown origin (FUO) in HIV-infected patients. Based on the outcomes of bone marrow examination of patients with FUO, we aimed to develop a predictive model for identifying the factors that can increase the diagnostic yield of bone marrow examination. DESIGN: For this retrospective cohort study, we enrolled HIV-infected patients, aged more than 15 years and diagnosed with FUO, at Songklanakarind Hospital in Southern Thailand, between January 2009 and December 2019. METHODS: Evaluations were based on bone marrow aspiration, biopsy, and culture; any missing data were imputed with regression imputation. RESULTS: Among the final 108 included patients, 44 (40.74%) showed positive bone marrow results. The diagnoses mainly comprised histoplasmosis, penicilliosis, and tuberculosis. Bone marrow examination led to treatment modifications in approximately 33% patients. Platelet count less than 150 000 cells/µl, alkaline phosphatase (ALP) level at least 200 U/l, and no previous antibiotic treatment were significantly associated with higher diagnostic yields. The HIV bone marrow (HIVBM) model, comprising of spleen size, hematocrit (Hct), platelet count before bone marrow examination, ALP level at admission, and previous antibiotic treatment, was generated as a nomogram to predict the diagnostic yield of bone marrow examination in HIV-infected patients with FUO. CONCLUSION: The results of this study indicate that the HIVBM model can be used to predict the diagnostic yield of bone marrow examination, and therefore assist in clinical decision-making regarding bone marrow procedures, to be performed for identifying the origin of fever in HIV-infected patients.

Multidisciplinary approach to diagnosis and management of fever of unknown origin: A case report.

INTRODUCTION: Fever of unknown origin (FUO) poses a diagnostic challenge, often requiring a systematic evaluation to uncover its elusive cause. This case study delves into the presentation of a 42-year-old Chinese male with persistent fever, muscle pain, and a perplexing rash. PATIENT CONCERNS: The patient's symptoms included a prolonged fever, chills, muscle pain, and throat discomfort, with a history of pulmonary tuberculosis. Initial diagnoses of upper respiratory infection and unspecified infection were followed by antibiotic treatments, yet the fever persisted, accompanied by an exacerbating rash. DIAGNOSIS: Extensive diagnostic investigations, including laboratory tests, imaging studies, and skin dermoscopy, provided valuable insights. The patient exhibited elevated inflammatory markers, hepatosplenomegaly, lymphadenopathy, and lung nodules. Differential diagnoses included adult-onset Still disease and drug-induced hypersensitivity syndrome. INTERVENTIONS: The patient received a series of antibiotic treatments, which initially had limited success. Upon considering an autoimmune etiology, corticosteroids were introduced, followed by cyclosporine. The patient exhibited a positive response to this immunosuppressive therapy. OUTCOMES: Treatment adjustments were made, and the patient responded positively to a combination of corticosteroids and cyclosporine. His fever subsided, and laboratory markers normalized. One month after discharge, the patient showed continued improvement. CONCLUSION: FUO cases often demand a multidisciplinary approach, considering rare and uncommon diseases. This case underscores the importance of thorough evaluation, collaboration between specialties, and vigilant monitoring of treatment responses. The patient's unique presentation emphasizes the need to consider drug-induced reactions, even when symptoms deviate from typical disease patterns, highlighting the complexities in diagnosing and managing FUO.

Mesenteric panniculitis as a possible cause of fever of unknown origin.

Mesenteric panniculitis is a non-neoplastic condition involving inflammation and fibrosis of the small bowel mesentery. We describe a man in his 60s who presented with 3 months of febrile episodes, confusion and weight loss. The diagnosis of mesenteric panniculitis had been established 2 weeks prior based on an abdominal computerized tomography scan. Extensive diagnostic investigations during his hospitalisation were unrevealing, and the symptoms were ultimately attributed to the mesenteric panniculitis. The fevers resolved over several weeks, and no further episodes have occurred since discharge. This case suggests that mesenteric panniculitis merits consideration in the differential diagnosis of fever of unknown origin.

Molecular Imaging of Infections: Emerging Techniques for Pathogen-Specific Diagnosis and Guided Therapy.

Evaluation of patients that may be infected is challenging. Imaging to identify or localize a site of infection is often limited because of the nonspecific nature of the findings on conventional imaging modalities. Available imaging methods lack the ability to determine if antibiotics are reaching the site of infection and are not optimized to follow response to therapy. Positron emission tomography (PET) is a method by which radiolabeled molecules can be used to detect metabolic perturbations or levels of expression of specific targets. The most common PET agent is the glucose analog 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG). 18F-FDG has some applicability to localizing a site of infection, but its lack of specificity limits its usefulness. There is a need for the development of pathogen-specific PET radiotracers to address the imaging shortcomings noted above. Preclinical and clinical progress has been made, but significant challenges remain.

Risk factors that are associated with adrenal insufficiency among patients with fever of unknown origin.

BACKGROUND: Adrenal insufficiency is one of the causes of fever of unknown origin (FUO). The purpose of this study is to find out risk factors that are associated with adrenal insufficiency in FUO patients. METHODS: This study was conducted retrospectively in a tertiary hospital with 846 beds in South Korea. All adult inpatients (age ≥19 years) who have requested a consult with the department of infectious disease for FUO between 1 July 20191 July 2019 and 30 June 202030 June 2020 were included in the study. Among them, those who underwent an adrenocorticotropic hormone (ACTH) stimulation test and had a fever of 37.8°C or higher within 48 hours of the ACTH stimulation test were finally included in the study subjects. RESULTS: A total of 202 FUO patients were enrolled and 61 (30.1%) were finally diagnosed with adrenal insufficiency. In a multivariate analysis, use of immunosuppressant within 3 months (OR 6.06, 95% CI 1.82-20.13, P = 0.003), use of corticosteroid within 3 months (OR 8.23, 95% CI 1.35-50.17, P = 0.022), sodium ≥ 136.7 (OR 3.43, 95% CI 1.49-7.88, P = 0.004), and calcium ≥ 8.4 (OR 0.31, 95% CI 0.14-0.71, P = 0.005) were proven to be factors associated with adrenal insufficiency in FUO patients. CONCLUSION: In conclusion, 30.1% of FUO patients were diagnosed with adrenal insufficiency. The risk factors that are associated with adrenal insufficiency in FUO patients were immunosuppressive prescription or systemic steroid prescription within 3 months, or with sodium ≥ 136.7 or calcium < 8.4.

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 article, 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.