[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.

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.

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.

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.

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.

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.

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

BACKGROUND: Metagenomic 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. METHODS: A 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. RESULTS: Compared 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. CONCLUSIONS: mNGS 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.

Clinical features of patients presenting with fever of unknown origin caused by non-tuberculous mycobacterium infection.

INTRODUCTION: Although non-tuberculous mycobacterium (NTM) infection accounts for only a small proportion of fever of unknown origin (FUO) cases, it has become a more common etiology in recent years. Therefore, we reviewed FUO patients with underlying NTM infection to better understand its clinical features. METHODOLOGY: The medical records of patients presenting with FUO and diagnosed with NTM infection admitted to Peking Union Medical College Hospital between January 2016 and June 2021 were reviewed. The clinical information of patients whose follow-up data were available were summarized. Specimens submitted for pathogenic identification were processed by mycobacterial culture, acid-fast staining, and mycobacterial nucleic acid detection. IBM SPSS Statistics v22.0 (SPSS, Inc., Chicago, IL, USA) was used for data analysis. RESULTS: Fifty-five FUO patients were diagnosed with NTM infection (55/785; 7.0% of FUO cases). Patients were mostly middle-aged men and had a relatively long disease course. Seven, 29, and 54 patients had previously no respondence to glucocorticoids, immunosuppressants, and multiple antibiotics, respectively; their inflammatory indexes were significantly increased; and there was no obvious risk of immunosuppression in this group, who were likely to be T.SPOT-TB negative (33/41; 80.5%). The most commonly identified NTM was Mycobacterium intracellulare followed by Mycobacterium chelonae/abscessus, Mycobacterium kansasii, and Mycobacterium avium. CONCLUSIONS: Microbiological investigations including culture, acid-fast staining, NTM nucleic acid examination, and next-generation sequencing were performed to confirm the diagnosis of NTM in FUO patients. FUO patients should screen for NTM infections so that this important etiology can be recognized, targeted treatments administered early, and outcomes improved.

Structured diagnostic scheme clinical experience sharing: a prospective study of 320 cases of fever of unknown origin in a tertiary hospital in North China.

BACKGROUND: There has been little research on the long-term clinical outcomes of patients discharged due to undiagnosed fevers of unknown origin (FUO). The purpose of this study was to determine how fever of unknown origin (FUO) evolves over time and to determine the prognosis of patients in order to guide clinical diagnosis and treatment decisions. METHODS: Based on FUO structured diagnosis scheme, prospectively included 320 patients who hospitalized at the Department of Infectious Diseases of the Second Hospital of Hebei Medical University from March 15, 2016 to December 31,2019 with FUO, to analysis the cause of FUO, pathogenetic distribution and prognosis, and to compare the etiological distribution of FUO between different years, genders, ages, and duration of fever. RESULTS: Among the 320 patients, 279 were finally diagnosed through various types of examination or diagnostic methods, and the diagnosis rate was 87.2%. Among all the causes of FUO, 69.3% were infectious diseases, of which Urinary tract infection 12.8% and lung infection 9.7% were the most common. The majority of pathogens are bacteria. Among contagious diseases, brucellosis is the most common. Non-infectious inflammatory diseases were responsible for 6.3% of cases, of which systemic lupus erythematosus(SLE) 1.9% was the most common; 5% were neoplastic diseases; 5.3% were other diseases; and in 12.8% of cases, the cause was unclear. In 2018-2019, the proportion of infectious diseases in FUO was higher than 2016-2017 (P < 0.05). The proportion of infectious diseases was higher in men and older FUO than in women and young and middle-aged (P < 0.05). According to follow-up, the mortality rate of FUO patients during hospitalization was low at 1.9%. CONCLUSIONS: Infectious diseases are the principal cause of FUO. There are temporal differences in the etiological distribution of FUO, and the etiology of FUO is closely related to the prognosis. It is important to identify the etiology of patients with worsening or unrelieved disease.

Metagenomic surveillance in Jinan, China, reveals serum microbiome and biochemistry features in fever of unknown origin (FUO) patients.

Here we aim to build up a metagenomics-centered surveillance on the infectious microbiome showing in the fever of unknown origin (FUO) patients. We collected venous blood, bronchoalveolar lavage fluid, cerebrospinal fluid, tissue block, sputum, bone marrow biopsy, and purulent liquid samples from 123 patients. Metagenomic sequencing (mNGS) for both DNA and RNA sequences was performed to profile the total pathogenic microbiome in the samples. A large pool of infectious or conditional infectious bacteria was found, belonging to Enterobacteriaceae, Staphylococcaceae (10.55%), Burkholderiaceae (10.05%), and Comamonadaceae (4.25%). The major virus families detected from mNGS analysis include Adenoviridae, Anelloviridae, Peribunyaviridae, Flaviviridae, and Herpesviridae, showing up in 34.96%, 47.37%, 30.89%, 5.69%, 3.25%, and 1.63% of patients, respectively. Using the Ward clustering method, two clusters of patients were organized: high-variety group and low-variety group. The patients in the high-variety group demonstrated higher levels of immune cells and inflammatory indicators such as lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase. The patients in the low-variety group showed higher levels of inflammatory lipids such as 13,14-dihy-15-keto PGE2 (fold > 10, P = 0.021); tetra-PGDM (fold = 5.29, P = 0.037); and 20-HETE (fold > 10, P = 0.02). The mNGS surveillance system demonstrated remarkable potential in preventing infectious diseases using mNGS data.

"The Fever Is Still There!": Workup and Management of Prolonged Fever.

Fever is one of the most common chief complaints that brings pediatric patients to seek medical care. Although fever is, in most cases, a physiologic response to a pathogen that has alerted the immune system, prolonged fever can be challenging to work up for the treating pediatrician. In addition to assessing causes of fever, pediatricians must also address the fears that many caregivers may have surrounding elevations in body temperature and provide education as to when fever becomes a concern. Fever can be classified by its duration as well as the presence or absence of associated symptoms. Fever without a source is defined as a fever that has been present for 1 week without a clear cause. Fever of unknown origin is a fever that has been present daily for 8 days or more without an apparent source. This article will walk through considerations for a clinician evaluating a pediatric patient with prolonged fever. [Pediatr Ann. 2023;52(4):e124-e126.].

Pyrexia of unknown origin (PUO) and the cost of care in a tertiary care institute in Sri Lanka.

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.

Classical fever of unknown origin in 21 countries with different economic development: an international ID-IRI study.

Fever of unknown origin (FUO) is a serious challenge for physicians. The aim of the present study was to consider epidemiology and dynamics of FUO in countries with different economic development. The data of FUO patients hospitalized/followed between 1st July 2016 and 1st July 2021 were collected retrospectively and submitted from referral centers in 21 countries through ID-IRI clinical research platform. The countries were categorized into developing (low-income (LI) and lower middle-income (LMI) economies) and developed countries (upper middle-income (UMI) and high-income (HI) economies). This research included 788 patients. FUO diagnoses were as follows: infections (51.6%; n = 407), neoplasms (11.4%, n = 90), collagen vascular disorders (9.3%, n = 73), undiagnosed (20.1%, n = 158), miscellaneous diseases (7.7%, n = 60). The most common infections were tuberculosis (n = 45, 5.7%), brucellosis (n = 39, 4.9%), rickettsiosis (n = 23, 2.9%), HIV infection (n = 20, 2.5%), and typhoid fever (n = 13, 1.6%). Cardiovascular infections (n = 56, 7.1%) were the most common infectious syndromes. Only collagen vascular disorders were reported significantly more from developed countries (RR = 2.00, 95% CI: 1.19-3.38). FUO had similar characteristics in LI/LMI and UMI/HI countries including the portion of undiagnosed cases (OR, 95% CI; 0.87 (0.65-1.15)), death attributed to FUO (RR = 0.87, 95% CI: 0.65-1.15, p-value = 0.3355), and the mean duration until diagnosis (p = 0.9663). Various aspects of FUO cannot be determined by the economic development solely. Other development indices can be considered in future analyses. Physicians in different countries should be equally prepared for FUO patients.

Adult-onset Still's disease and fever of unknown origin in India.

Despite an essential differential diagnosis for fever of unknown origin (FUO) in young adults, adult-onset Still's disease (AOSD) is infrequently considered and remained underdiagnosed in low-middle-income countries. The present study analyzed the clinical, serological, radiological, and pathological characteristics of AOSD presented as FUO in India. A hospital-based retrospective study of patients aged > 13 years admitted with FUO and later diagnosed with AOSD in Postgraduate Institute of Medical Education and Research, Chandigarh (India), was conducted between January 2014 and December 2020. Petersdorf and Beeson's criteria were used to define FUO. The diagnosis of AOSD was made based on Yamaguchi's criteria. Twenty-seven patients (median age 26 years, 14 females) were enrolled. All presented with intermittent fever with a median duration of 10 weeks. The typical features of AOSD at admission were arthralgia (n = 24), hepatosplenomegaly (n = 21), spiking fever ≥ 39 °C (n = 19), lymphadenopathy (n = 18), typical rash (n = 17), and sore throat (n = 11). Leukocytosis (n = 25) and neutrophilia (n = 19) were frequent. Hyperferritinemia was universal (range, 700-145,003 ng/ml; ≥ 2000, n = 23). At admission, AOSD was suspected in only nine FUO cases, while tuberculosis (n = 16), undifferentiated connective tissue disorder (n = 14), and lymphoproliferative disorder (n = 11) were common diagnostic possibilities. Crispin et al. clinical scale detected AOSD in only 15 (55.5%) FUO patients. Whole-body imaging (n = 27), including fluorodeoxyglucose positron emission tomography (n = 12), demonstrated reticuloendothelial organ-system involvement and serositis. Seventeen (63%) patients had macrophage activation syndrome at the time of AOSD diagnosis. AOSD FUO presents with typical but nonspecific features; thus, early differentiation from common causes (e.g., tuberculosis, lymphoma) is difficult. Macrophage activation syndrome is common in AOSD with FUO presentation.