Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome that can present as prolonged fever of unknown origin (FUO). We describe the case of a 26-year-old woman who presented with two months of intermittent high-grade fever, joint pain, and transient salmon-colored skin rashes. Laboratory investigations revealed cytopenia, elevated triglycerides, abnormal liver enzymes, and a markedly elevated serum ferritin level (>10,000 ng/mL). Extensive evaluation for infectious and autoimmune causes was negative. Whole-body PET-CT demonstrated diffusely increased marrow activity with small mesenteric lymph nodes, while bone marrow examination confirmed hemophagocytosis. The patient met six of the HLH-2004 diagnostic criteria, and her HScore was calculated at 228, indicating a high probability of HLH. In the absence of any identifiable trigger, a diagnosis of idiopathic secondary HLH was made. She was treated with dexamethasone monotherapy, which led to rapid resolution of fever, normalization of laboratory parameters, and sustained remission at three-month follow-up. This case underscores the importance of considering HLH early in adults with unexplained fever, cytopenia, and extreme hyperferritinemia, and highlights that corticosteroid monotherapy may be sufficient in selected idiopathic cases.

Background: giant cell arteritis (GCA) is the most frequent large vessel vasculitis, affecting both male and female patients older than 50 years old. Opposite to the cranic involvement (common carotid arteries and their branches) that may debut with headache and visus loss, the extra-cranic involvement (aorta and its branches) is more subtle, leading to a delayed diagnosis, causing the development of aneurisms and dissections [1-3]. Usually, these are late disease complications (after 10 years) but can be found even at diagnosis [1-3]. Case report: a 68-year-old woman, ex-smoker, comes to visit because of a 4-month history of daily fever (up to 38.5°C) with shivers and night sweats, myalgias, fatigue and weight loss. Blood tests showed high neutrophil and platelet count, with persistent inflammation (CRP 35 mg/L). To rule out an occult infection, the patient had been thoroughly screened with blood cultures, urine cultures, treponemic tests, which all came back negative. Being affected by a fever of unknown origin (FUO), the patient was admitted to our Clinic to undergo further testing from which no sign of autoimmunity emerged. Given the development of a persistent frontal headache, even though no other arteritis symptoms were present, an ultrasonographic study of the temporal, axillary, and carotid arteries was performed, showing no halo sign. Because of the persistence of fever and inflammation without explanation, a PET-CT and an echocardiography (to rule out infective endocarditis) were performed and, since GCA was still highly suspected, a temporal artery biopsy was scheduled. PET-CT (Figure 1) showed an intense FDG avidity along the full length of the aortic wall and the carotid and axillary arteries while the echocardiography found a dilation of the aortic root with valve insufficiency and no sign of endocarditis. Granulomatous inflammation suggesting GCA was found in the biopsy specimen of the temporal artery. The aortic dilation was studied performing a CT angiography that confirmed the enlargement of the aortic root and arch and showed a focal dissection 4 cm wide (Figure 2). Glucocorticoid therapy was immediately started and tapered for 8 weeks, alongside tocilizumab, leading to the resolution of fever and inflammation. In the meantime, heart surgeons successfully performed a replacement of the aortic arch. Histological analysis of the aortic wall confirmed the GCA diagnosis (Figure 3). Conclusions. PET-CT and temporal artery biopsy should always be a part of the FUO diagnostic work-up, even when signs or symptoms suggesting GCA are absent. They turn out to be crucial to timely diagnose the disease and may help early identify severe and potentially fatal complications like aneurisms and aortic dissections that, despite being more frequent in the late course of the disease, can also be found at its debut4. This has important therapeutic and prognostic implications.

Severe fever with thrombocytopenia syndrome (SFTS), caused by SFTS virus (SFTSV), is an emerging tick-borne disease in East Asia. SFTS monitoring has been carried out since 2010 in mainland China, but no confirmed human cases or infected vectors had been reported from the northern regions of Hebei Province. We intensified surveillance in this area by collecting serum samples from patients with fever of unknown origin (FUO) and ticks from local habitats. Subsequently, all collected samples were screened for SFTSV by qRT-PCR. SFTSV RNA was detected in two patient sera from Chengde (2.2%). In six, positive ticks were detected among the Haemaphysalis verticalis (8.6%) collected from Zhangjiakou; no positive ticks were detected among the ticks collected from Chengde. Complete viral genomes were recovered from positive tick samples via next-generation sequencing and subjected to a suite of bioinformatic analyses. Two complete genomes from Haemaphysalis verticalis formed a distinct clade with an Inner Mongolia strain across L/M/S (bootstrap = 1.0) and separate from genotypes A–F; pairwise p-distances to genotypes A–F were >0.11 across L/M/S, supporting designation of a distinct genotype. We designate this lineage as genotype G; no credible recombination was detected. Based on the L segment, molecular-clock analyses dated the genotype G lineage to the late 13th century, predating the crown age of genotypes A–F (~18th century) by more than 400 years. We provide the first evidence of SFTSV circulation in northern Hebei and identify a novel, deeply divergent lineage. This finding confirms the co-circulation of distinct viral lineages (G and F) within the province and provides critical new insights into the virus’s diversity and evolutionary history. These results expand the known range and genetic diversity of SFTSV, underscoring the need for enhanced surveillance and ecological investigation in emerging regions. It is necessary to strengthen public health education, improve the early diagnosis and treatment ability of medical workers, and provide a scientific basis for targeted public health interventions.

Fever of unknown origin (FUO): a 7-year clinical experience, etiological distribution, and diagnostic approaches

Neonatal human herpesvirus type 6 (HHV-6) infection is an extremely rare disease. HHV-6 is a unique virus because it is able to integrate into human chromosomes to be further transmitted vertically from parent to offspring. In humans, HHV-6 is associated with a wide range of clinical manifestations and, in children, may present as roseola infantum, febrile seizures, aphthous stomatitis, mononucleosis-like syndrome, or fever of unknown origin. This article reports a rare case of congenital HHV-6 infection in a newborn. To date, both Russian and international publications provide very limited descriptions of such cases, which, in our opinion, reflects a significant knowledge gap among neonatologists regarding this condition. We discuss the clinical forms of HHV-6 infection in neonates, rare case presentations, and current approaches to diagnosis and treatment.

Background: Fever of unknown origin (FUO) in children remains a diagnostic challenge due to heterogeneous etiologies. This study investigated the etiological distribution, long-term outcomes of undefined cases, and laboratory predictors that differentiate infectious from non-infectious etiologies. Methods: We retrospectively evaluated 87 children (1 month-18 years) hospitalized with fever > 38.3 °C for ≥7 days with no detectable source (2018-2024). Patients were categorized into five groups: infectious, inflammatory, neoplastic, miscellaneous, and undefined. Comparisons between these groups were performed in terms of age, laboratory values, and duration of fever using the Kruskal-Wallis test and one-way ANOVA. Demographic, clinical, laboratory, and follow-up data were compared. ROC analysis and binary logistic regression identified predictors of non-infectious etiologies. Results: Infectious diseases (42.5%) and inflammatory disorders (19.5%) were the most common causes, while 17.2% of cases remained undefined. The median age was 60 months. Rash (31%) and fatigue (27.5%) were the most common complaints on admission. The undefined group showed complete spontaneous resolution during a median 63-month follow-up, with no recurrence or new diagnoses, except for one patient. Miscellaneous etiologies accounted for 14.9% of cases, and more than half of these were newly diagnosed primary immunodeficiencies. C-reactive protein and ferritin levels were significantly higher in the inflammatory disease group compared to the groups with unknown and infectious etiologies. In the binary logistic regression analysis, longer fever duration combined with elevated ferritin level was a combined predictor of non-infectious causes (AUC = 0.718). Conclusions: Infectious and inflammatory conditions predominate in pediatric FUO, yet a subset of cases resolve spontaneously and follow a benign course. The combination of fever duration and ferritin count may aid early differentiation of non-infectious etiologies, supporting more focused diagnostic approaches. Given the notable proportion of primary immune deficiencies, especially in populations with high consanguinity, early immunologic screening should be incorporated into FUO evaluation protocols.

Fever of Unknown Origin (FUO) remains a diagnostic challenge, defined by prolonged fever lasting for more than three weeks without a clear cause despite a minimum of three days of hospital investigations or three outpatient visits at least. This study aims to explore the etiologies and potential predictive factors for classic FUO in Italy, updating prior data from earlier studies. Conducted from October 2019 to June 2023, this prospective, multi-center registry enrolled 188 patients from 25 Italian hospitals, assessing demographics, comorbidities, and clinical characteristics in relation to FUO causes. Results indicated that 72.1% of cases reached a final diagnosis, with etiologies primarily in non-infectious inflammatory (31.8%), infectious (25.7%), and neoplastic (8.4%) categories, while 27.9% remained undiagnosed. Younger patients (under 55years) were more likely to lack a definitive diagnosis, suggesting that advanced investigations might benefit early this patient population. Comorbid conditions like chronic obstructive pulmonary disease and cardiovascular symptoms were associated with infectious causes, whereas musculoskeletal and dermatologic signs suggested a non-infectious inflammatory origin. The overall mortality rate was 2.8% at a 6-month follow-up. This study highlights the need for improved diagnostic tools to address the substantial number of undiagnosed FUO cases. Trial registration: NCT05254522 ClinicalTrials.gov identifier.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare autoimmune neuroinflammatory disorder. While it typically presents as optic neuritis, myelitis, or acute disseminated encephalomyelitis (ADEM), its manifestation as pyrexia of unknown origin (PUO) with subsequent meningitis is extremely rare. We report a 17-year-old male who presented with persistent fever and headache, without focal neurological deficits. Extensive infectious workup was inconclusive. Cerebrospinal fluid (CSF) analysis revealed mild pleocytosis, and empirical antibiotics were initiated without clinical improvement. A repeat CSF analysis demonstrated worsening pleocytosis, prompting an expanded autoimmune and neuroinflammatory panel. MOG-IgG antibodies were detected in both serum and CSF, confirming the diagnosis of MOGAD. The patient responded well to high-dose corticosteroids followed by mycophenolate mofetil for maintenance therapy. This case highlights the importance of considering MOGAD in patients with unexplained fever and headache with inflammatory CSF. Early recognition and prompt immunotherapy initiation are essential for optimal outcomes. A favorable outcome was observed following timely immunotherapy.

Abstract Introduction/Objective Persistent fever in immunocompromised patients can be a diagnostic challenge, especially when common infectious causes are ruled out. Visceral leishmaniasis, though rare outside endemic regions, should remain a consideration in such cases due to its potentially fatal nature if missed. Methods/Case Report We present a 20-year-old male with a history of sarcoidosis on chronic immunosuppressive therapy, who presented with persistent fever, weight loss, gum hypertrophy, and generalized lymphadenopathy. Examination revealed pallor and hepatosplenomegaly. Family history was notable for liver cirrhosis and tuberculosis. Initial workup included differential diagnoses such as pyrexia of unknown origin, malignancy, toxoplasmosis, and tuberculosis. A right axillary lymph node biopsy showed granulomatous inflammation, morphologically favoring toxoplasmosis. However, bone marrow examination revealed hypercellular marrow (60–80%), trilineage hematopoiesis, dyserythropoietic changes, and infiltration by organisms morphologically consistent with Leishmania. The presence of kinetoplasts on Giemsa/Wright stain confirmed the diagnosis, clearly distinguishing it from other mimics. Numerous macrophages packed with amastigotes indicated a high parasitic burden, and PCR testing corroborated the findings. Results NA Conclusion This case highlights the diagnostic utility of bone marrow examination in evaluating prolonged fever when initial findings are inconclusive and highlights the need to maintain a broad differential, even in non-endemic regions, for timely and life-saving diagnosis.

Infiltrative anterior mediastinal lesions are reportedly a characteristic computed tomography (CT) finding of thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome. The present study aimed to explore their potential clinical value in TAFRO syndrome. The present study reviewed cases of TAFRO syndrome and idiopathic multicentric Castleman disease-not otherwise specified (iMCD-NOS) diagnosed at Tokyo Metropolitan Tama Medical Center between 2007 and 2024. Body CT images were analyzed for the presence of anasarca, organomegaly, lymphadenopathy, and anterior mediastinal and lung lesions. Additionally, CT images of patients who were admitted for a fever of unknown origin (FUO) between 2018 and 2024 and later received a diagnosis of a malignancy or autoimmune disorder were assessed for these findings. Twelve, 11, and 22 patients with TAFRO syndrome, iMCD-NOS, and FUO, respectively, were included. Seven patients with TAFRO (58%) and one patient with iMCD-NOS (9%) had an anterior mediastinal lesion. Only one of the 22 patients with a FUO had an anterior mediastinal lesion (5%). Anterior mediastinal lesions were more frequently observed in patients with TAFRO syndrome than in those with iMCD-NOS or FUO. This finding may be useful in diagnosing TAFRO syndrome and distinguishing it from iMCD-NOS and FUO.

In this review we summarize the current knowledge on fever of unknown origin (FUO). Fever of unknown origin remains a diagnostic challenge even despite increasing diagnostic possibilities since its first definition. Uniform definition of FUO is pivotal to correctly select patients that benefit from the extensive workup that may be needed. The number of conditions associated with FUO is still increasing. Epidemiologic differences and differences in diagnostic possibilities are a challenge when comparing outcomes from cohorts with different epidemiologic backgrounds. The diagnostic protocol that was proposed as early as 2007, with a central role for 18F-FDG-PET/CT, still remains the golden standard for the workup of FUO. Early use of new diagnostic modalities, including the use of metagenomic next generation sequencing and artificial intelligence, may shorten the diagnostic delay. In patients remaining undiagnosed, second opinion in an expert center can be considered, especially when therapeutic trials are considered. An increasing subset of patients presents with absent inflammatory parameters. Correct evaluation within a febrile episode is important in patients with intermittent disease, but these patients may also suffer from habitual or functional hyperthermia. We advise to let go of these terms and introduce the criteria for temperature elevation with missing inflammatory parameters (TEMP) syndrome.

Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are among the most challenging diagnoses in clinical routine. [18F]FDG positron emission tomography/computed tomography (PET/CT) is a valuable diagnostic tool, particularly when conventional imaging and laboratory investigations fail to identify the root cause. While its diagnostic accuracy in FUO/IUO settings is high, several issues still remain to be addressed. Long axial field of view PET/CT and the availability of novel radiopharmaceuticals for molecular imaging may significantly advance the field of nuclear medicine and molecular imaging in FUO/IUO. This scoping review conforms to the "Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews Checklist". An extensive literature search of PubMed/MEDLINE database was performed to find relevant published articles on the use of LAFOV PET/CT and novel radiotracers in FUO/IUO settings. LAFOV PET/CT provides faster whole-body imaging, improved sensitivity, and the ability to perform ultra-low-dose scans. These benefits are particularly valuable for special populations, such as pediatric patients, ICU patients, and pregnant women, where motion artifacts, radiation exposure, and procedural complexity are major concerns. Additionally, novel radiotracers, including FAPI and CXCR4-targeted agents, offer promising specificity for inflammatory or infectious etiologies beyond FDG, potentially improving diagnostic accuracy and reducing false positives. LAFOV PET/CT and emerging radiopharmaceuticals represent major advancements in the diagnostic workup of FUO/IUO. They enhance lesion detection, reduce scan burden, and may improve outcomes, particularly in vulnerable populations. Further clinical studies are needed to standardize protocols and validate these tools in broader clinical practice.

Giant hepatic hemangioma: A rare cause of fever of unkonwn origin fever

A 23-year-old woman presented with refractory anemia and a 1-month history of relapsing fever. The patient had been followed up at another hospital for fever of unknown origin and refractory anemia for 2 years. Upon admission to our hospital, repeated body temperature measurements and a nurse’s inspection revealed that the patient had been artificially heating the external auditory canal where the temperature was measured to simulate fever. No temperatures exceeding 38℃ were recorded after the nursing staff removed objects capable of altering measurements, confirming factitious fever as the cause. We report this case to highlight the importance to clinicians who care for patients with fever of unknown origin despite careful and appropriate evaluation.

Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are diagnostically challenging conditions due to their diverse etiologies and non-specific presentations. Despite advances in diagnostic techniques, a significant proportion of cases remain unexplained, often leading to delays in treatment and increased healthcare burden. In recent years, [18F]FDG-PET/CT has emerged as a powerful diagnostic tool offering whole-body metabolic imaging, particularly valuable in the early stages of disease when structural changes may be absent. In this review a literature search was conducted in PubMed and Web of Science for original studies on the use of FDG-PET/CT in adults with FUO/IUO published between January 2005 and June 2025. The authors evaluated the diagnostic yield and clinical impact of [18F]FDG-PET/CT in adults with FUO/IUO based on 56 studies comprising over 7,400 patients. The [18F]FDG-PET/CT was helpful in up to 90% of cases when both true-positive and true-negative results were considered. Furthermore, [18F]FDG-PET/CT led to changes in patient management in a substantial proportion of cases, particularly when used early in the diagnostic algorithm. It demonstrates robust diagnostic performance, guiding therapeutic decisions, and guide subsequent interventions hereby avoiding futile examinations. Despite its growing recognition, standardization in study design and outcome reporting is needed to further consolidate its role in clinical guidelines.

18F FDG PET/CT plays an important role in the investigation of fever of unknown origin (FUO), particularly after failure of conventional investigations to identify the source. However, its diagnostic yield is highly influenced by a wide range of factors including patient preparation, physiological variant, and treatment related factors. This review aims to provide an overview of the most common causes experienced in clinical practice, and how to avoid common pitfalls that may affect scan interpretation. For instance, elevated blood glucose levels, prolonged steroid therapy and recent interventions may reduce scan sensitivity, while artefacts from injection sites and brown fat uptake may mimic sites of disease. Careful preparation - including dietary modification, activity restriction and appropriate access selection - combined with clinical correlation and review of non-attenuation corrected images enhances interpretation, and as always, multidisciplinary discussions remain key.

To provide an overview of the diagnosis and management of patients with anaplasmosis, also known as human granulocytic anaplasmosis, a lesser-known tick-borne illness increasing in prevalence in Canada. A PubMed search was conducted between October 2024 and March 2025 using the search terms anaplasmosis and tick-borne illness with a focus on epidemiology, diagnosis, and management. Levels of evidence for treatment recommendations ranged from II to III, with most available data coming from case reports, case series, retrospective studies, and systematic reviews. Tick-borne illnesses are becoming more prevalent in Canada due to the effects of climate change. Anaplasmosis is a lesser-known tickborne illness transmitted by the same vectors as Lyme disease. Patients with anaplasmosis commonly present with a nonspecific febrile illness, often without a distinctive rash. Leukopenia, thrombocytopenia, and mild transaminitis are commonly seen in bloodwork results. Family physicians in Canada should familiarize themselves with this relatively new entity and include it in their differential diagnosis when evaluating patients with fever of unknown origin. In such cases, polymerase chain reaction testing for anaplasmosis, alongside Lyme disease serology, should be considered. Patients with either disease respond well to treatment with doxycycline. With the expanding range of tick populations in Canada, the risk of anaplasmosis, along with other tick-borne illnesses, is becoming more prevalent. Increased awareness among family physicians is critical for timely diagnosis. Prompt recognition and treatment can reduce the risk of complications.

the article highlights the clinical and epidemiological features of infectious mononucleosis in adults based on an analysis of 222 patients who underwent treatment at the infectious diseases department of St. Michael’s Clinical Hospital in Kyiv from 2017 to 2023. Infectious mononucleosis is primarily caused by the Epstein-Barr virus, although other etiological agents include cytomegalovirus and human herpesvirus type 6. The aim of the study was to assess the incidence and epidemiological characteristics of infectious mononucleosis in adults over a six-year observation period. The research included a retrospective analysis of medical records, clinical manifestations, and laboratory-confirmed diagnoses. The study demonstrated that the incidence of infectious mononucleosis remained stable from 2017 to 2019, followed by a complete absence of cases in 2020 – 2021, likely due to the impact of pandemic restrictions related to coronavirus disease 2019. In 2022–2023, a resurgence of cases was observed, indicating the return of viral circulation. The average annual incidence rate was calculated at 34 cases per year, which aligns with epidemiological data reported in the literature. Among the analyzed patients, 57.3% were men and 42.7% were women, with the highest prevalence observed in the age group of 18 to 29 years, accounting for 70.3% of cases. The study found that Epstein-Barr virus was detected in 57.1% of male and 42.9% of female patients, whereas cytomegalovirus was more frequently identified in women (10.8%) than in men (4.5%). A significant proportion of patients (77.02%) were hospitalized with alternative preliminary diagnoses, primarily lacunar tonsillitis (36.5%), as well as follicular tonsillitis (2.5%), hepatitis (1.5%), meningitis (1.75%), and fever of unknown origin (0.5%). These findings indicate that infectious mononucleosis in adults often presents with a polymorphic clinical picture, which may complicate early diagnosis. Statistical analysis was performed using Student’s t-test, Wilcoxon W-test, the Chi-square method, and Spearman’s correlation coefficient, with a significance threshold of p=0.05. The results emphasize the need for improved differential diagnosis strategies, drawing clinicians’ attention to other manifestations of infectious mononucleosis, such as fever, generalized lymphadenopathy, and hepatosplenomegaly. The study highlights the role of infectious mononucleosis as a significant clinical disease in adults and substantiates the need for continuous epidemiological monitoring.

Lymphomatoid granulomatosis is an extralymphatic angio-invasive B-cell-associated lymphoproliferative disease. It primarily affects the lungs, followed by the skin, CNS, renal, and liver, and rarely involves the musculoskeletal system. Here we report a young man with pyrexia of unknown origin in whom FDG PET/CT demonstrated an unusual combination of CNS, lung, and musculoskeletal involvement mimicking diffuse metastasis. He was diagnosed with lymphomatoid granulomatosis, grade I, on a guided biopsy of the lung nodule.

BackgroundThe etiology of fever of unknown origin (FUO) is complex, and early diagnosis of FUO is important for determining the method of treatment, but there are no uniform diagnostic criteria. This study aimed to evaluate the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in differentiating the etiological types of FUO and to develop a predictive model.MethodsA total of 456 FUO patients with baseline 18F-FDG-PET/CT data were enrolled. The etiological categories were classified into neoplastic diseases (NDs) and nonneoplastic diseases (NNDs) and then classified into infectious diseases (IDs) and noninfectious inflammatory diseases (NIIDs). Continuous variables were compared with the Mann-Whitney U test, and categorical variables were compared with the Chi-squared test. Features were screened via the above method, and multivariate logistic regression (Bonferroni correction) was subsequently applied to construct two models: a clinical model (laboratory data only) and a combined model (laboratory + PET/CT data), with corresponding nomograms generated. The model performance was assessed by calculating the area under the receiver operating characteristic curve (AUC), which was compared via the Delong test.ResultsTo differentiate between NDs and NNDs, five PET/CT variables [asymmetrical distribution of hypermetabolic lymph nodes, maximum standardized uptake value (SUVmax) in the bone marrow, SUVmax in the spleen, splenomegaly, and focal liver lesion], and three laboratory variables [white blood cell (WBC) count, platelet count (PLT) and lactate dehydrogenase (LDH)] (all P<0.05) were selected to construct the models. To differentiate between IDs and NIIDs, three PET/CT variables (short diameter of the lymph node, hypermetabolic spleen, and focal spleen lesion), one laboratory variable (WBC count) and age (all P<0.05) were selected to construct the models. In the validation group, the combined model (AUC =0.742) did not demonstrate significant improvement over the clinical model—either in differentiating NDs from NNDs (AUCcombined =0.742 vs. AUCclinical =0.680; P=0.080) or in distinguishing ID from NIID (AUCcombined =0.737 vs. AUCclinical =0.678; P=0.111).ConclusionsThis study demonstrated the diagnostic value of 18F-FDG PET/CT in differentiating etiological types of FUO. However, the addition of 18F-FDG PET/CT did not significantly enhance the ability of clinical models to distinguish between NDs and NNDs or between IDs and NIIDs. Further validation in future studies is warranted.