Fever of unknown origin: A 12-year case series in Colombia.

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. METHODOLOGY: 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.

The Diagnostic Yield of [18F]FDG-PET/CT in a Heterogeneous In-Patient Population with Suspected Infection or Inflammation Is Comparable to Findings in Patients with Classic Fever of Unknown Origin.

INTRODUCTION: 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.

An Unusual Case of Fever in Paralytic Ileus.

Still's disease is frequently a condition of exclusion for patients with an unidentified cause of fever. Accompanying symptoms typically include fever, arthralgia, and a transient skin rash. The underlying pathophysiology indicates an autoimmune origin. Diagnosis is primarily clinical, often utilizing the Yamaguchi criteria. The case in question involves a 19-year-old male presenting with high-grade fever and paralytic ileus. The patient received intravenous glucocorticoids and cyclophosphamide, resulting in a rapid clinical improvement. During the follow-up, tofacitinib was initiated based on the clinical response observed.

Recommendations for Updating Fever and Inflammation of Unknown Origin From a Modified Delphi Consensus Panel.

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.

Fever of unknown origin revealing testicular nocardiosis: a case report and literature review.

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. CASE PRESENTATION: 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.

Spider Bite Presenting as Fever, Macrophage Activation Syndrome and a Skin Ulcer.

Introduction: Fever of unknown origin (FUO) refers to a condition of prolonged increased body temperature, without identified causes. The most common cause of FUO worldwide are infections; arthropod bites (loxoscelism) should be considered in view of the spread of the fiddleback spider. Loxoscelism can present in a cutaneous form (a necrotic cutaneous ulcer) or in a systemic form with fever, haemolytic anaemia, rhabdomyolysis and, rarely, macrophage activation syndrome (MAS). For this suspicion, it is important to have actually seen the spider. Case description: A 71-year-old man was admitted to our department because of intermittent fever, arthralgia and a necrotic skin lesion on his right forearm that appeared after gardening. Laboratory tests were negative for infectious diseases, and several courses of antibiotics were administered empirically without clinical benefit. Whole-body computed tomography showed multiple colliquative lymphadenomegalies, the largest one in the right axilla, presumably of reactive significance. A shave biopsy of the necrotic lesion was performed: culture tests were negative and histological examination showed non-specific necrotic material, so a second skin and lymph node biopsy was performed. The patient developed MAS for which he received corticosteroid therapy with clinical/laboratory benefit. Cutaneous and systemic loxoscelism complicated by MAS was diagnosed. Subsequently, the second biopsy revealed morphological and immunophenotypic findings consistent with primary cutaneous anaplastic large cell lymphoma (PC-ALCL). Conclusions: Skin lesions and lymphadenomegalies of unknown origin should always be biopsied. It is very common to get indeterminate results, but this does not justify not repeating the procedure to avoid misdiagnosis. LEARNING POINTS: In case of necrotic skin lesions with fever, malignancy (and in particular cutaneous lymphoma) should always be considered.Misdiagnosis of loxoscelism is common. Definitive diagnosis requires the identification of the responsible spider.It is frequent to obtain inconclusive results from biopsies, but this does not justify not repeating the procedure to avoid misdiagnosis.

The hidden burden of melioidosis in Nepal: a paradigm for the urgent need to implement a simple laboratory algorithm to detect Burkholderia pseudomallei in low-resource endemic areas.

Melioidosis, an emerging infectious disease caused by the Gram-negative bacillus Burkholderia pseudomallei, is massively underdiagnosed in many low- and middle-income countries. The disease is clinically extremely variable, has a high case fatality rate, and is assumed to be highly endemic in South Asian countries, including Nepal. The reasons for underdiagnosis include the lack of awareness among clinicians and laboratory staff and limited microbiological capacities. Because costly laboratory equipment and consumables are likely to remain a significant challenge in many melioidosis-endemic countries in the near future, it will be necessary to make optimum use of available tools and promote their stringent implementation. Therefore, we suggest that health facilities in resource-poor countries, such as Nepal, introduce a simple and low-cost diagnostic laboratory algorithm for the identification of B. pseudomallei cultures. This screening algorithm should be applied specifically to samples from patients with fever of unknown origin and risk factors for melioidosis, such as diabetes. In addition, there could also be a role of low-cost, novel, promising serological point-of-care tests, which are currently under research and development.

A Rare Presentation of Systemic Lupus Erythematosus in a Patient With Fever of Unknown Origin.

This case presents a 23-year-old male with a rare presentation of lupus as fever of unknown origin (FUO). The patient's clinical symptoms, examination findings, and laboratory results painted a complex picture that necessitated considering macrophage activation syndrome and adult-onset Still's disease but ultimately led to the diagnosis of systemic lupus erythematosus. The case emphasizes the importance of including lupus in the differential diagnosis of FUO given the associated risks and higher mortality rates in this demographic, especially in males. Understanding lupus prevalence and classification criteria aids in diagnosis, highlighting the importance of a systematic approach for FUO and emphasizing timely intervention for improved patient outcomes.

[18F]FDG PET/CT for identifying the causes of fever of unknown origin (FUO).

Fever of unknown origin (FUO) continues to be a challenging diagnosis in clinical medicine. It has more than 200 known causes, including infections, autoimmune diseases, neoplasia, and other miscellaneous disorders. Despite the development of a wide range of diagnostic tools, a specific diagnostic algorithm for FUO is not yet available. However, [18F]FDG PET/CT, which yields information on cellular metabolism, in addition to details of organ anatomy, has been shown to be successful in the FUO investigation. This study highlights the uses of [18F]FDG PET/CT in diagnosing various causes of FUO. [18F]FDG PET/CT has been increasingly used to detect septic infections, sterile inflammatory processes, and malignancies, occupying a significant portion of the known causes of FUO. It has led to a more definitive identification of the etiology of FUO and accurate clinical management. However, more in-depth studies are crucial to understanding if [18F]FDG PET/CT can be used in the work-up of FUO.

Deciphering the association between biopsy-confirmed systemic small vessel vasculitis and Epstein-Barr virus-positive polymorphic B-cell lymphoproliferation.

The Epstein-Barr virus (EBV) is associated with various lymphoproliferative disorders (LPD). Additionally, EBV infection has correlated with diverse autoimmune diseases. However, the association between EBV and systemic small vessel vasculitis (SVV) remains controversial. Here, we report a case of SVV with pauci-immune glomerulonephritis accompanied by an EBV-positive polymorphic B-cell LPD, not otherwise specified. The intricate distinction between EBV-positive B-cell LPD and SVV was difficult, as both diseases demonstrated similar clinical presentations. Lymph node and kidney biopsies facilitated the accurate diagnosis of these two conditions. The administration of high-dose prednisolone, combined with rituximab, proved efficacious, with no instances of relapse over the subsequent 2-year period. This case indicates an association between EBV-positive B-cell LPD and SVV. The diligent execution of biopsies is a crucial diagnostic and interpretive strategy, generating precise comprehension of this condition and guiding its appropriate therapeutic management.

Droplet digital PCR aids in the diagnosis of children with fever of unknown origin --A typical case report.

Many clinical conditions can cause fever of unknown origin (FUO) in children, but the etiological diagnosis remains challenging despite the variety of inspection methods available at present. This study aims to investigate the effectiveness of droplet digital polymerase chain reaction (ddPCR) in identifying pathogens in children with FUO as a novel application. A 7-month-old boy failed to obtain etiology evidence for his disease through various tests. After collecting peripheral blood for ddPCR analysis, Staphylococcus aureus and Escherichia coli were detected, and Sanger sequencing confirmed the pathogens. During the disease, the child developed septic arthritis and osteomyelitis in the femur. Despite the patient's fever being removed, his limb activity improving, and inflammatory biomarkers decreasing, avascular necrosis of the femoral head remained after targeted antibiotic treatment and surgery. If the patient had undergone ddPCR analysis at an early stage, it may be possible to avoid sequelae. ddPCR helps identify pathogens in the diagnosis of children with FUO and could be a promising complementary tool.

Pulmonary and Urologic Sarcoidosis as a Cause of Intermittent Fever of Unknown Origin.

Diagnosing fever of unknown origin (FUO) presents a substantial challenge due to its potential association with various diseases affecting different organs. In 1961, Petersdorf and Beeson initially defined FUO as a condition characterized by a temperature exceeding 38.3 °C on at least three occasions over a minimum three-week period. Despite a week of inpatient investigation, a definitive diagnosis remains unclear.  Sarcoidosis, a granulomatous disease impacting multiple systems, is among the causes of FUO. While the lungs are commonly affected, any organ can be involved, leading to diverse manifestations and clinical courses. Diagnosis relies on clinicopathologic findings and the exclusion of alternative causes of granulomatous disease. The hallmark of sarcoidosis is the development of granulomas in affected organs. Here, we present the case of a 61-year-old man with a history of recurrent spontaneous periurethral abscesses who underwent multiple urological interventions. He developed FUO during hospitalization following treatment for the infectious condition.

Dengue en paciente de 32 días de vida. Reporte de un caso poco habitual / Dengue fever in a 32-day-old patient. A rare case report

El dengue es una enfermedad viral transmitida por la picadura del mosquito Aedes aegypti. El comportamiento del dengue en Argentina es epidémico; la mayoría de los casos se observan en los meses de mayor temperatura. Hasta la semana epidemiológica (SE) 20/2023, se registraron en Argentina 106 672 casos; se vieron afectadas 18 de las 24 provincias que conforman el país. Dentro de los principales grupos de riesgo, se incluyen los menores de 2 años. Reconocer los signos, síntomas e identificar los factores de riesgo es fundamental para el manejo de casos con mayor riesgo de gravedad. Presentamos el caso de una paciente de 32 días de vida que se internó por síndrome febril sin foco, con diagnósticos diferenciales de meningitis viral y sepsis, evolucionó con leucocitosis, plaquetopenia, hipoalbuminemia, asociado a exantema y edemas. Se llegó al diagnóstico de dengue por la clínica, epidemiologia e IgM positiva.

Dengue fever is a viral disease transmitted by the Aedes aegypti mosquitoes. In Argentina, dengue fever is an epidemic disease; most cases are reported during the hot months.Until epidemiological week (EW) 20/2023, 106 672 cases were reported across 18 of the 24 provinces of Argentina. Children younger than 2 years are among the main groups at risk. Recognizing signs and symptoms and identifying risk factors is fundamental for the management of cases at a higher risk of severity. Here we describe the case of a 32-day-old female patient who was hospitalized due to febrile syndrome without a source, who had a differential diagnosis of viral meningitis and sepsis and progressed to leukocytosis, thrombocytopenia, hypoalbuminemia in association with rash and edema. The diagnosis of dengue fever was established based on clinical, epidemiological, and positive IgM data.

Barking up the wrong tree: Vascular tree-in-bud due to intravascular lymphoma.

A 59-year-old previously healthy woman presented with a six-month history of fever, nonproductive cough, and weight loss. The cause of these symptoms remained obscure despite a thorough, month-long hospitalization. On presentation, she was normotensive with a pulse of 98 beats/minute, respiratory rate of 20 breaths/minute, and a temperature of 39.4C. She was emaciated. Physical examination was notable for faint bibasilar crackles on lung auscultation. Initial laboratory testing revealed pancytopenia. Peripheral smear demonstrated normocytic, normochromic anemia without immature cells or schistocytes. Other notable laboratory findings included elevated levels of lactate dehydrogenase, elevated ferritin, and elevated levels of fasting serum triglycerides. A comprehensive laboratory evaluation for connective tissue disease was negative. Plain chest radiography was normal while computed tomography (CT) of the chest demonstrated sub-centimeter nodules in a branching centrilobular pattern as well as in a peri-lymphatic distribution without associated lymphadenopathy or organomegaly. The above constellation of laboratory abnormalities raised concern for hemophagocytic lymphohistiocytosis (HLH). Soluble IL-2 (CD25) receptor levels were markedly elevated. Bronchoscopy with transbronchial biopsies of the right lower lobe was performed, revealing intravascular lymphoma associated with HLH. Our case emphasizes the need for clinicians to consider vascular causes of tree - in-bud nodules in addition to the conventional bronchiolar causes. The case also is a reminder of the need to conduct an exhaustive search for malignancy, in patients with HLH.

Unexplained recurrent high fever observed in a depressed adolescent.

BACKGROUND: Depressive episodes in adolescents are often accompanied by various physical symptoms, but few studies have explored the association between depression and fever, This case study is the first to report the relationship between unexplained recurrent high fever and depression. CASE PRESENTATION: H is a 15 year old adolescent female currently in junior year. 2 + months ago, H gradually felt depressed after a class change. Around the time, the patient suddenly developed chills with no obvious trigger and fever. H was treated with anti-infective and anti-viral treatments all of which did not show significant improvement. No significant abnormality was seen in any of the related examinations. Considering that the patient's anxiety, depression and somatic symptoms were obvious during the course of the disease, she was given venlafaxine hydrochloride extended-release capsule 75 mg/d; tandospirone citrate capsule 10 mg Bid; alprazolam tablets 0.4 mg qn to improve mood and sleep; supplemented with transcranial repetitive magnetic stimulation therapy 2 times/d; visible light therapy 1 time/d and psychological counseling once. Over the 6 days of treatment, the patient's body temperature gradually returned to the normal range and her mood improved significantly. CONCLUSION: Depression should be considered a potential cause of unexplained recurrent fevers in adolescents, even when the temperature is significantly outside the normal range.

EANM consensus document on the use of [18F]FDG PET/CT in fever and inflammation of unknown origin.

PURPOSE: Patients with fever and inflammation of unknown origin (FUO/IUO) are clinically challenging due to variable clinical presentations with nonspecific symptoms and many differential diagnoses. Positron emission tomography/computed tomography (PET/CT) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is increasingly used in FUO and IUO, but the optimal diagnostic strategy remains controversial. This consensus document aims to assist clinicians and nuclear medicine specialists in the appropriate use of [18F]FDG-PET/CT in FUO and IUO based on current evidence. METHODS: A working group created by the EANM infection and inflammation committee performed a systematic literature search based on PICOs with "patients with FUO/IUO" as population, "[18F]FDG-PET/CT" as intervention, and several outcomes including pre-scan characteristics, scan protocol, diagnostic yield, impact on management, prognosis, and cost-effectiveness. RESULTS: We included 68 articles published from 2001 to 2023: 9 systematic reviews, 49 original papers on general adult populations, and 10 original papers on specific populations. All papers were analysed and included in the evidence-based recommendations. CONCLUSION: FUO and IUO remains a clinical challenge and [18F]FDG PET/CT has a definite role in the diagnostic pathway with an overall diagnostic yield or helpfulness in 50-60% of patients. A positive scan is often contributory by directly guiding treatment or subsequent diagnostic procedure. However, a negative scan may be equally important by excluding focal disease and predicting a favorable prognosis. Similar results are obtained in specific populations such as ICU-patients, children and HIV-patients.

[Infections and fever]. / Infektion und Fieber.

Fever can be due to infectious or noninfectious causes and results from the body's natural response to exogenous or endogenous pyrogens. Laboratory tests including complete blood count, differential blood count, C­reactive protein, erythrocyte sedimentation rate and procalcitonin do not have sufficient sensitivity and specificity to definitively detect or rule out an infectious (bacterial, viral, parasitic) cause of fever. Blood cultures should be carried out when bacteremic or septic illnesses are suspected. Fever is not always present in infections and can be absent, especially in older and immunocompromised patients. If fever is suspected, core temperatures should be taken, e.g., rectally, orally or invasively. Depending on the clinical situation, infectious causes must be excluded as the most likely cause of an acutely occurring fever. The investigation of long-standing fever (fever of unknown origin, FUO) can be complex and some infectious diseases should first be ruled out, whereby a syndromic classification often helps to clarify the cause of the fever.

Pyrexia of Unknown Origin: A Report of Two Cases.

Pyrexia of unknown origin (PUO) is a prolonged fever lasting several weeks without an identifiable cause despite extensive medical evaluation. Many a time, its cause remains largely unknown even after collecting a detailed medical history, conducting comprehensive physical assessments, and performing various standard laboratory tests and imaging procedures. This case series presents two cases of pyrexia of unknown origin. The first case includes a unique and uncommon presentation of non-Hodgkin's lymphoma. In the second case, the patient's fever remained unexplained after various investigations and treatments. The two documented cases of PUO presented in this report aim to contribute to the understanding of its diverse etiology and diagnostic challenges. By highlighting unique presentations and diagnostic dilemmas, the cases aim to promote awareness and facilitate timely recognition and appropriate management of PUO.

Multidisciplinary Exploration of Unknown Oral Lesions With Accompanying Oral Verrucas of the Tongue: A Case Report.

A 64-year-old African American male with a history of hypertension and type II diabetes mellitus presented with unexplained upper lip lacerations after several frequent episodes of hemoptysis. Following the upper lip lacerations were several weeks of intermittent unknown episodic fevers. The patient, challenged by impaired mobility, exhibited an array of symptoms, including severe upper lip pain with lacerations and white patches on the tongue. Laboratory findings indicated thrombocytopenia and anemia, with positive tests for both influenza A and B. Despite completing Tamiflu, the patient experienced recurrent fevers. Imaging revealed gastrointestinal abnormalities, leading to the initiation of nystatin and a multi-antibiotic regimen without significant fever resolution. A subsequent tongue biopsy revealed verruca lesions, and acyclovir was initiated. Despite this, the patient developed lip and facial blisters. Negative results from cytomegalovirus (CMV) deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) prompted a shift in focus to managing persistent fevers, ultimately controlled with naproxen but without discoverable cause. This case underscores the diagnostic challenge posed by unexplained fevers in an elderly patient with oral manifestations. The protracted course and evolving symptoms emphasize the intricacies of managing such cases, highlighting the need for continued investigation and collaboration across medical disciplines in navigating complex clinical scenarios.