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Finding the cause of fever of unknown origin can sometimes be a real challenge. We present an adolescent whose diagnosis was achieved after 4 months of fever onset by performing a positron emission tomography (PET)–CT. A young woman presented with prolonged, intermittent fever along with inflammatory and iron deficiency anaemia, loss of weight and abdominal and chest pain. First investigational studies showed high-titre positive antinuclear antibodies, extractable nuclear antibodies and anti-Sjögren's-syndrome-related antigen a autoantibodies (anti-SSA), and mild pericardial effusion and aortic regurgitation, but without meeting criteria for systemic lupus erythematosus. She had maxillary sinusitis that did not resolve with antibiotics. Further study displayed elevated calprotectin in faeces. After normal abdominal ultrasound and CT, an intestinal MRI showed thickening of the terminal ileum, orienting towards an inflammatory bowel disease. A colonoscopy showed only minor macroscopic changes. A PET–CT scan was finally requested, which exhibited a diffuse increase in metabolism in the wall of the thoracic and abdominal aortas, suggesting Takayasu’s arteritis.

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18F-FDG PET/CT, 67Ga-citrate and white blood cell (WBC) scintigraphy are molecular imaging techniques currently used in the diagnostic workup of fever of unknown origin. However, it is unknown which technique fits which patient group best. A systematic literature search has been performed for original articles regarding the use of molecular imaging in fever of unknown origin. A total of 820 eligible studies were screened of which 63 articles evaluating 5094 patients met the inclusion criteria. 18F-FDG PET/CT provided good diagnostic accuracy (with a weighted mean sensitivity, specificity, positive predicting value, negative predictive value, accuracy and helpfulness of 84.4%, 61.8%, 80.7%, 67.8%, 76.3%, and 61.1%, respectively). Even within specific patient groups such as children, elderly, patients with connective tissue diseases, patients on renal replacement therapy, and HIV-infected patients, 18F-FDG PET/CT provided good diagnostic values. For 67Ga-citrate scintigraphy, the weighted mean sensitivity, specificity, positive predictive value, negative predictive value, and helpfulness were 42.2%, 80.3%, 82.4%, 41.9%, and 42.2%, respectively. WBC scintigraphy shows a weighted mean sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 73.5%, 86.3%, 79.1%, 82.4%, and 79.5%, respectively. However, compared to 67Ga-citrate and WBC scintigraphy, significantly more research has been performed using 18F-FDG PET/CT and 18F-FDG PET/CT has the advantage of relatively short procedural duration; it is therefore the preferred molecular diagnostic imaging technique. 67Ga-citrate and WBC scintigraphy can only be considered if 18F-FDG PET/CT is not available.

Evidence suggests that the symptom duration may affect the occurrence of certain fever (FUO) and inflammation (IUO) of unknown origin associated conditions. It is unclear if this could potentially guide diagnostic evaluations. We examined the association between symptom duration and diagnostic and prognostic outcomes in FUO/IUO.We retrospectively analyzed a cohort of adult patients meeting criteria for FUO/IUO from a tertiary care center in Belgium between 2000 and 2019. The association between symptom duration and outcomes of interest were estimated by Cox proportional hazards models.Among 602 patients who met criteria for FUO/IUO (mean age 54 years, 43% female), 132 (22%) and 68 (11%) had symptoms for 3-12 months and12 months, respectively. There were no significant differences in diagnosis or all-cause mortality between a symptom duration of3 months and 3-12 months. In contrast, those who had a symptom duration of12 months were less likely to receive a final diagnosis (aHR 0.42, 95% CI 0.30-0.60), in particular a diagnosis of infectious disorders (aHR 0.29, 95% CI 0.12-0.74), malignancies (aHR 0.11, 95% CI 0.03-0.46), and miscellaneous conditions (aHR 0.22, 95% CI 0.07-0.71), but no significant differences were seen in noninfectious inflammatory disorders (aHR 0.74, 95% CI 0.48-1.15) or all-cause mortality (aHR 0.55, 95% CI 0.19-1.54).The symptom duration may be used to guide the diagnostic workup among patients with FUO and IUO, in particular those with longstanding symptoms.

As a greater number of households have pets, the likelihood of zoonotic infections can rise too. Although in most healthy individuals these infections are self-limiting, they are more serious and can lead to adverse outcomes in the immunocompromised. There is minimal information available for the immunocompromised patient who are pet owners or on pet handling. We report a case of cat scratch disease-related sepsis in an immunocompromised patient. This case illustrates the need for a detailed history, including a pet history, in immunocompromised patients presenting with fever of unknown origin and the need for UK-based information for the immunocompromised on pet care and risks associated with having a pet.

In endemic areas, histoplasmosis should always be considered as a differential diagnosis in a patient presenting with fever of unknown origin, chronic fatigue, adrenomegaly and hyperpigmentation. Early diagnosis and prompt institution of antifungal therapy is imperative to prevent mortality as

Aim: To explore [fluorine-18]-fluoro-2-deoxy-d-glucose positron-emission-tomography/computed tomography (18FDG-PET/CT) in patients where standard investigations were non-diagnostic. Methods: We reviewed medical records of previously healthy children who had 18FDG-PET/CT performed at Copenhagen University Hospital in 2015–2020 due to unexplained fever. Results: Thirty-five of 819 paediatric 18FDG-PET/CT were performed due to unexplained fever. The final diagnoses were malignancy (11%), infections (23%), inflammatory diseases (43%) and miscellaneous (26%). 18FDG-PET/CT was diagnostic in six cases with Takayasu's arteritis, tuberculosis, Langerhans cell histiocytosis and Ewing sarcoma. Sixteen cases had focal 18FDG-uptake, but 18FDG-PET/CT could only differentiate malignancy, infection and inflammation in three cases. In six cases with inflammatory diseases and no focal signs, PET/CT was normal except increased non-specific 18FDG-uptake in bone marrow and spleen in five cases. One case was false positive (suspicion of appendicitis) and two false negative (leukaemia and inflammatory disease). Conclusion: 18FDG-PET/CT was diagnostic, or contributed to the diagnosis, in several children with unexplained fever referred to a tertiary centre. Challenges comprised (i) only increased non-specific 18FDG-uptake in bone marrow and spleen in half of cases with inflammatory diseases, (ii) no differentiation between complicated infections, malignancy and inflammation in most cases with focal processes and (iii) a small risk of false positive and false negative results.

Pyrexia of unknown origin (PUO) and its aetiology vary considerably according to geography. We conducted a retrospective study to update our knowledge of PUO in Pakistan. PUO was defined as a febrile illness of >3 weeks’ duration, a temperature of >38.3°C, and >3 outpatient visits or 3 days’ hospitalization. Infection was the cause in 47.1%, malignancy in 23.1%, noninfectious inflammatory disease in 21.8%, miscellaneous causes in 1.2%, and in 6.8%, the cause of the fever was not found.

Numerous studies have clarified the usefulness of 18F-fluorodeoxyglucose (FDG)-PET/CT (positron emission tomography) for diagnosing the cause of fever of unknown origin (FUO). Various types of disease can cause FUO, but the cause remains unknown in a certain proportion of FUO, even when the advanced diagnostic methodologies are used. FDG-PET/CT is regarded as a second-line modality in the diagnostic process of FUO, and its potential to identify the cause of FUO will be maximized when the appropriate clinical considerations are understood. Accordingly, this review presents basic knowledge regarding FUO, and reports the current status of FDG-PET/CT applied to diagnosing the cause of FUO, including diagnostic performance, test protocols, possible factors influencing the diagnostic result, outcomes, and cost-effectiveness. This knowledge will enable effective future use of FDG-PET/CT to improve outcomes in patients with FUO.

Background Early antibiotic discontinuation according to the Fourth European Conference on Infections in Leukaemia (ECIL-4) recommendations is not systematically applied in high-risk neutropenic patients with haematological malignancies. Methods A retrospective multicentre observational study was conducted over 2 years to evaluate the safety of early antibiotic discontinuation for fever of unknown origin (FUO) during neutropenia after induction chemotherapy or HSCT, in comparison with a historical cohort. We used Cox proportional hazards models, censored on neutropenia resolution, to analyse factors associated with febrile recurrence. Results Among 147 included patients in the ECIL-4 cohort, mainly diagnosed with acute leukaemia (n = 104, 71%), antibiotics were discontinued during 170 post-chemotherapy neutropenic episodes. In comparison with the historical cohort of 178 episodes of neutropenia without antibiotic discontinuation, no significant differences were observed regarding febrile recurrences [71.2% (121/170) versus 71.3% (127/178), P = 0.97], admission in ICUs [6.5% (11/170) versus 11.2% (20/178), P = 0.17], septic shock [0.6% (1/170) versus 3.9% (7/178), P = 0.07] and 30 day mortality [1.4% (2/147) versus 2.7% (4/150), P = 0.084]. In the ECIL-4 cohort, the rate of bacteraemia in case of febrile recurrence was higher [27.1% (46/170) versus 11.8% (21/178), P Conclusions After an FUO episode in high-risk neutropenia, compliance with ECIL-4 recommendations for early antibiotic discontinuation appears to be safe and mucosal damage was associated with febrile recurrence and bacteraemia. Prospective interventional studies are warranted to assess this strategy in high-risk neutropenic patients.

Clinicians usually easily recognize cranial manifestations of giant cell arteritis (GCA) such as new-onset headache, jaw claudication, scalp tenderness, and abrupt changes in visual acuity or blindness; however, when presented with an aberrant clinical course, the diagnosis becomes more elusive. In addition to temporal arteries and other extracranial branches of the carotid arteries, large vessel vasculitis (LVV) can also affect other blood vessels including coronary arteries, aorta with its major branches, intracranial blood vessels, and hepatic arteries.Over time, the scope of the symptoms typically associated with LVV has broadened and includes cases of fever of unknown origin accompanied with other constitutional symptoms that can mimic a range of neoplastic and infectious diseases. In up to half of patients with atypical LVV, liver enzyme level elevations with a cholestatic pattern have been observed. Alkaline phosphatase level and γ-glutamyl transferase level elevations tend to be more prevalent in those LVV patients with vigorous inflammatory responses, particularly in those with fever and other nonspecific constitutional symptoms. These patients also have more profound anemia and thrombocytosis. With the exception of rare instances of vasculitides and granulomas affecting the liver tissue, liver biopsy is generally of little help and primarily shows nonspecific changes of fatty liver.In this article, we review 3 patients who were eventually diagnosed with atypical LVV. The diagnosis was confirmed with temporal artery biopsy in 2 patients and with positron emission tomography/computed tomography in 1 patient. The common hepatic abnormality observed in all patients was the elevation of alkaline phosphatase level, which tended to respond rapidly to initiation of immunosuppressive treatment.

To explore the significance of Fluorine-18 labeled fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in diagnosing connective tissue diseases (CTDs) in fever of unknown origin (FUO) or inflammation of unknown origin (IUO) patients.Clinical and image data of 242 consecutive FUO/IUO patients who underwent PET/CT examination and eventually diagnosed CTDs were retrospectively analyzed, including distribution of diseases, clinical characteristics, and PET/CT imaging findings. The role of FDG PET/CT in differential diagnosis of CTDs was evaluated through clinical questionnaire survey.Patients diagnosed as CTDs accounted for 48.1% of FUO/IUO patients. Among them, adult-onset Still's disease was most frequently diagnosed. Other common diseases included systemic vasculitis, undifferentiated connective tissue disease, rheumatoid arthritis, idiopathic inflammatory myopathy, systemic lupus erythematosus, and polymyalgia rheumatica. On FDG PET/CT examination, 97.9% of the patients had positive findings. Inflammatory lesions were detected in 66.5% and non-specific abnormal uptakes were found in 31.4%. Detected lesions distributed consistently with corresponding susceptible organs and tissues in various diseases. Clinical questionnaire results shown that FDG PET/CT excluded malignant tumors, focal infections, or other typical CTDs in 45.5% of the patients; indicated important diagnostic clues or appropriate biopsy sites in 20.6% of patients; and directly suggested the diagnosis of a CTD in 33.1% of patients.FDG PET/CT could reveal inflammatory lesions in organs and tissues that reflect the clinical characteristics in different CTDs, thus providing an objective evidence for differential diagnosis, classification, and treatment decision of these diseases. Key Points • FDG PET/CT is a useful tool for differential diagnosing connective tissue diseases among patients with fever of unknown origin/inflammatory of unknown origin.

Listeriosis is an infective complication that primarily affects pregnant women, patients at extremes of age or those with weakened immune systems. Ingestion of food contaminated with Listeria monocytogenes is the most common source of infection, causing self-limiting illness in immunocompetent hosts but associated with invasive infection and high mortality in high-risk patient groups. Milder illness presents as gastroenteritis with fever, diarrhoea, nausea and vomiting common in the 7 days post exposure. Invasive infection, characterised by bacteraemia and encephalitis, can develop in high-risk patients. Fetal loss is a major complication of listeriosis during pregnancy. Penicillin-based therapy (high dose penicillin or amoxicillin) in combination with gentamicin is advised for invasive infection; co-trimoxazole may be considered for patients intolerant to penicillin. Vulnerable individuals, notably pregnant women, should be counseled on appropriate preventative strategies including avoiding foods commonly contaminated with L. monocytogenes, such as soft ripened cheeses, pate, cooked chilled meats, unpasteurised milk, and ready to eat poultry unless thoroughly cooked.

A Boy with Fever and Developmental Regression A 12-month-old boy with Hirschsprung’s disease was admitted with fever, generalized weakness, intermittent diffuse rash, and regression of crawling. He...

Background Thiamine metabolism dysfunction syndrome 4 (THMD4, OMIM #613710) is an autosomal recessive inherited disease caused by the deficiency of SLC25A19 that encodes the mitochondrial thiamine pyrophosphate (TPP) transporter. This disorder is characterized by bilateral striatal degradation and progressive polyneuropathy with the onset of fever of unknown origin. The limited number of reported cases and lack of functional annotation of related gene variants continue to limit diagnosis. Results We report three cases of encephalopathy from two unrelated pedigrees with basal ganglia signal changes after fever of unknown origin. To distinguish this from other types of encephalopathy, such as acute necrotizing encephalopathy, exome sequencing was performed, and four novel heterozygous variations, namely, c.169G>A (p.Ala57Thr), c.383C>T (p.Ala128Val), c.76G>A (p.Gly26Arg), and c.745T>A (p.Phe249Ile), were identified in SLC25A19. All variants were confirmed using Sanger sequencing. To determine the pathogenicity of these variants, functional studies were performed. We found that mitochondrial TPP levels were significantly decreased in the presence of SLC25A19 variants, indicating that TPP transport activities of mutated SLC25A19 proteins were impaired. Thus, combining clinical phenotype, genetic analysis, and functional studies, these variants were deemed as likely pathogenic. Conclusions Exome sequencing analysis enables molecular diagnosis as well as provides potential etiology. Further studies will enable the elucidation of SLC25A19 protein function. Our investigation supplied key molecular evidence for the precise diagnosis of and clinical decision-making for a rare disease.

Background Myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelinating disorders (MOGAD) are increasingly being recognized in the pediatric age group. Over time, unusual presentations have expanded the clinical presentation. We report 12 cases of MOGAD where prolonged fever (PF) was an important part of the symptom complex during the course of the illness. Methods After initial recognition of this atypical clinical presentation, more patients were recruited over 2 years and followed up prospectively. Results Eight of twelve patients had no clinical/imaging evidence of demyelination until much later in the course. Three clinical presentations recognized were fever of unknown origin (4 of 12), aseptic meningitis (4 of 12), and PF seen concurrently with established acute demyelination syndrome (4 of 12). Leukocytosis, raised inflammatory markers, and cerebrospinal fluid pleocytosis were almost universal. The first two presentations frequently caused diagnostic confusion, as MOGAD was not considered until several weeks after disease onset. The third group was more a therapeutic conundrum on how to manage the PF. Early seizures without encephalopathy were not uncommon and were probably independent of the later-appearing demyelination. Conclusions This case series highlights PF as an important component of the pediatric MOGAD symptom complex. MOGAD could be considered in the differential diagnosis of these clinical presentations.

Better Late than Never - Fever of Unknown Origin in a Patient with a Prosthetic Valve

Parents’ confidence regarding their children’s fever is a key factor in its management and there is still unnecessary anxiety and associated antipyretic overuse. The FeverApp application collects naturalistic real-time data on febrile infections and educates parents on fever management. Logistic regression examined the associations between (1) parental confidence and (2) antipyretics use with fever relevant parameters. First entry data of 3721 children (mean age 21 months; SD 22.97) was assessed. A total of 58.0% of parents felt confident upon first fever documentation. Warning signs [OR = 0.49, 95% CI: 0.40–0.61], dehydration [OR = 0.65, 95% CI: 0.52–0.81], fever [OR = 0.67, 95% CI: 0.57–0.80] and having a female child [OR = 0.77, 95% CI: 0.66–0.90] had the highest negative association with parental confidence. Antipyretics were used initially in 14.7% of children. Fever had the highest positive [OR = 2.58, 95% CI: 1.89–3.50] and well-being the highest negative association with antipyretic use [OR = 0.37, 95% CI: 0.22–0.63). In the first entry data, parental confidence was related to children’s health condition in a reasonable medical manner. The use of antipyretics was mostly associated with febrile temperature, but also low well-being. Thus, associations were partly in accordance with recent guidelines.

Neoplastic causes account for approximately 10% to 20% cases of PUO (pyrexia of unknown origin). The mechanisms by which malignancies induce fever are not fully understood. The release of pyrogenic cytokines either directly from tumor cells or from macrophages responding to tumor are likely to play a major role, which acts on the hypothalamus, causing a change in the thermostatic set point. We present a case of recurrent glioblastoma multiforme, who presented with PUO. 18F-FDG-labeled leukocyte PET/CT scan done for localization of infective focus demonstrated significant tracer accumulation at the periphery of the recurrent brain lesion. Subsequent excisional biopsy from the lesion was suggestive of noninfected recurrent glioblastoma multiforme.

The patient presented to our clinic from out of state in October 2018. Previously, in 2014, he underwent an elective left total hip arthroplasty with a ceramic-on-polyethylene prosthesis for osteoarthritis. The surgery and recovery were uneventful. In November 2014, hives developed on his upper arms. Within weeks, the hives spread to his trunk and thighs but spared his face, palms, and soles. The symmetric, nonpruritic, nonpainful rash was without angioedema. The hives initially persisted for 5 days, followed by resolution for several days.

A previously healthy, fully immunized 7-year-old girl presented with a 7-week history of daily fevers and a worsening cough with persistently elevated inflammatory markers. Before admission, she had an unrevealing outpatient workup by infectious disease, rheumatology, pulmonology, and otorhinolaryngology for her fever and other symptoms. Multiple courses of antibiotics had no effect, but brief courses of steroids seemed to modestly alleviate her symptoms. At an outside hospital, a computed tomography neck and chest scan revealed mediastinal lymphadenopathy. She was subsequently transferred to the authors’ institution. Her examination was notable for a febrile, tired-appearing girl in respiratory distress with a muffled voice and inspiratory stridor. Her laboratory tests revealed leukocytosis with left shift, microcytic anemia, and hypoalbuminemia, as well as elevated inflammatory markers, ferritin, and fecal calprotectin. Her peripheral smear, uric acid, and lactate dehydrogenase were all within normal limits. Infectious study results, including blood and urine cultures, cytomegalovirus serologies, and Bartonella serologies were negative. On the second read of her outside computed tomography imaging, her lymphadenopathy was felt to be nonpathologic. Based on a recommendation by rheumatology, an ophthalmologic examination was obtained, which revealed bilateral anterior uveitis; however, rheumatologic laboratory test results returned negative. Her fevers continued, and inflammatory markers remained elevated despite antibiotics. On day 6 of hospitalization, she developed worsening respiratory distress, necessitating intubation and transfer to the ICU. Repeat laryngoscopy and bronchoscopy revealed severe purulent tracheitis; however, throat cultures remained sterile. Her clinical deterioration without identification of an offending organism prompted additional evaluation for a systemic etiology.

Background: Early antibiotic discontinuation has been advocated in haematology patients with fever of unknown origin during chemotherapy-induced neutropenia, but its safety is unknown. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment. Methods: This non-inferiority, open-label, multicentre, randomised trial was done in six hospitals in the Netherlands. Adult patients (≥18 years) who were treated with intensive chemotherapy or haematopoietic stem-cell transplantation (HSCT) for a haematological malignancy, and had fever of unknown origin during high-risk neutropenia (9/L expected for ≥7 days) were eligible. After onset of fever, patients received either 500 mg intravenous imipenem-cilastatin four times a day or 1000 mg intravenous meropenem three times a day. Between 48 h and 72 h of treatment, participants were randomly assigned (1:1) by a computer-generated sequence to receive a short-term (72 h [60–84]; short treatment group) or extended (≥9 days until being afebrile for 5 days or neutrophil recovery; extended treatment group) carbapenem regimen. The composite primary endpoint was treatment failure, defined as recurrent fever or a carbapenem-sensitive infection between day 4 and day 9 and septic shock or respiratory failure or death from day 4 until neutrophil recovery. The study was designed to assess the non-inferiority of the short treatment compared with the extended treatment regimen, with a non-inferiority margin of 10%. The primary outcome was adjudicated by an independent outcome committee, who were masked to treatment allocation, and was analysed in the intention-to-treat and per-protocol populations. The trial is completed and registered with ClinicalTrials.gov, NCT02149329. Findings: Between Dec 1, 2014, and July 1, 2019, 281 patients were included in the intention-to-treat analysis: 144 (51%) patients were assigned to the short treatment group and 137 (49%) to the extended treatment group. Median age was 59 years (IQR 52–65); 109 (39%) patients were women and 172 (61%) were men; 205 (73%) patients received HSCT. In the intention-to-treat analysis, 28 (19%) of 144 patients in the short treatment group versus 21 (15%) of 137 patients in the extended treatment group had treatment failure (adjusted risk difference [ARD] 4·0% [90% CI –1·7% to 9·7%]; p=0·25). In the per-protocol analysis (n=225), 24 (23%) of 104 patients in the short treatment group and 19 (16%) of 121 patients in the extended treatment group had treatment failure (ARD 7·3% [0·3% to 14·9%]; p=0·11). The most common grade 3–5 infection-related adverse events were mucositis (23 [20%] of 114 adverse events in the short treatment group vs 28 [29%] of 98 adverse events in the extended treatment group), fever of unknown origin (20 [18%] vs 16 [16%] events), and bacteraemia (15 [13%] vs 13 [13%] events). The number of serious adverse events were higher in the short treatment group (23 [16%] of 144 patients) than in the extended treatment group (14 [10%] of 137 patients), due to an increased rate of readmission (17 [12%] patients in the short treatment group vs ten [7%] in the extended treatment group). Death before 30 days after neutrophil recovery occurred in five (3%) participants in the short treatment group: two due to progressive leukaemia, two due to candidaemia, and one due to Enterococcus faecium bacteraemia and drug-induced pneumonitis. One (1%) patient died in the extended treatment group due to candidaemia. None of the deaths were related to carbapenem-sensitive infections. Interpretation: Early discontinuation of carbapenem treatment in patients with febrile neutropenia of unknown origin does not result in increased treatment failure. Our study supports short treatment if patients are afebrile after 3 days of carbapenem treatment. However, because secondary analyses suggested that serious adverse events and all-cause mortality occurred more often in patients who are persistantly febrile the short treatment group, we recommend vigilance for non-susceptible pathogens and early resumption of empirical therapy in patients who are deteriorating. Funding: The Netherlands Organisation for Health Research and Development and Fonds NutsOhra.

Background Fever of unknown origin (FUO) has been difficult to diagnose in pediatric clinical practice. With the gradual change in the disease spectrum, genetic factors have received increasing attention. Limited studies have shown an association between FUO and chromosomal abnormalities. In this study, we investigated the clinical and genetic characteristics of patients with FUO presenting with chromosomal abnormalities in a Chinese pediatric cohort. Results Chromosomal abnormalities were detected in 5.5% (8/145) of the patients with FUO. Six patients with inflammatory fever presented with pharyngitis/amygdalitis (4/6), oral aphthous ulcer (2/6), digestive symptoms (3/6), developmental delay (4/6) and elevated C-reactive protein levels (6/6) during fever. These patients were often considered to have systemic inflammatory diseases, such as Behcet’s disease or systemic juvenile idiopathic arthritis. Trisomy 8, 7q11.23 dup, 3p26.3-p26.1 del/17q12 dup, 22q11.21 del, and 6q23.3-q24.1 del were identified in patients with inflammatory fever. The TNFAIP3 gene was included in the 6q23.3-q24.1 deletion fragment. Two patients with central fever were characterized by facial anomalies, developmental delay, seizures and no response to antipyretic drugs and were identified as carrying the de novo 18q22.3-q23 del. By performing a literature review, an additional 19 patients who had FUO and chromosomal abnormalities were identified. Trisomy 8, 6q23.2-q24.3 del and 18q22.3-q23 del were reported to present as fever, similar to the findings of our study. Conclusions We emphasized the important role of detecting chromosomal abnormalities in patients with FUO, especially in patients with systemic inflammatory manifestations or developmental delay. Identifying chromosomal abnormalities may change the diagnosis and management of patients with FUO.

Fever of unknown origin is a common differential diagnostic problem in medicine. More than 60 years have passed since the first established definition of the disease, and despite constant development and improvement of diagnostic procedures, the differential diagnosis and choosing adequate therapy still remains a challenge in this patient population. The medical literature lists at least 200 diseases that may manifest with fever of unknown origin, and it encompasses a wide clinical spectrum. This symptom is present in approximately 1.5-3% of hospitalized patients. In recent decades, not only the concept of fever of unknown origin has changed several times, but the recommended differential diagnostic procedures as well. Positron emission tomography is one of the latest imaging procedures that also contributes to establishing the correct diagnosis. The purpose of this publication is to provide an overview of different diseases which might cause fever of unknown origin, and the most frequently used diagnostic algorithms, moreover to highlight the importance of positron emission tomography in the evaluation of the aetiology of fever of unknown origin. Orv Hetil. 2022; 163(49): 1935-1942.Az ismeretlen eredetű láz gyakori differenciáldiagnosztikai probléma az orvostudományban. A kórkép első definiálása óta eltelt több mint 60 év, és a diagnosztikai eljárások állandó fejlődése és tökéletesítése ellenére továbbra is kihívást jelent a kezelőorvos számára a differenciáldiagnosztika és a megfelelő terápia megválasztása. Az orvosi szakirodalom legalább 200 betegséget tart számon, amely ismeretlen eredetű lázzal manifesztálódhat, és ezek igen széles klinikai spektrumot ölelnek fel. A hospitalizációt igénylő betegek esetében hozzávetőlegesen 1,5–3%-ban van jelen ismeretlen eredetű láz. Az elmúlt évtizedekben többször változott nemcsak az ismeretlen eredetű láz definíciója, de az ajánlott kivizsgálási protokoll is. A pozitronemissziós tomográfia a legmodernebb képalkotó eljárások közé tartozik, s nagyban hozzájárul a bonyolult esetek összefüggéseinek feltárásához és a helyes diagnózis felállításához. A jelen közlemény célja, hogy átfogó képet nyújtson az ismeretlen eredetű lázat kiváltó betegségekről, a leggyakrabban használt diagnosztikai algoritmusokról, valamint rávilágít a pozitronemissziós tomográfia fontos szerepére e betegségek okainak feltárásában. Orv Hetil. 2022; 163(49): 1935–1942.

Objective To summarize the clinical features of spontaneous remission in classic fever of unknown origin (FUO). Methods Medical records of 121 patients diagnosed with FUO at admission in Peking Union Medical College Hospital between January 2018 and June 2018 were reviewed retrospectively. Patients who were discharged without etiological diagnoses were followed for 2 years. The clinical features and outcomes of these patients were summarized. Multivariate

U radu je prikazan slučaj bolesnice s Crohnovom bolesti koja se u relapsu bolesti prezentirala s piodermom gangrenozum šake.

Background Human brucellosis has become one of the major public health problems in China, and increases atypical manifestations, such as fever of unknown origin (FUO), and misdiagnosis rates has complicated the diagnosis of brucellosis. To date, no relevant study on the relationship between brucellosis and FUO has been conducted. Methods We retrospectively reviewed the medical charts of 35 patients with confirmed human brucellosis and prospectively recorded their outcomes by telephone interview. The patients were admitted to the Second Affiliated Hospital of Nanchang University between January 01, 2013 and October 31, 2019. Patient data were collected from hospital medical records. Results The percentage of males was significantly higher than that of female in FUO (78.95% vs. 21.05%, P P P P Conclusion Brucellosis is predominantly FUO admission in a non-endemic area of China, accompanied by irregular fever and toxic hepatitis. Careful examination of the epidemiological history and timely improvement of blood and bone marrow cultures can facilitate early diagnosis and prevent misdiagnosis.

The aim of this study was to evaluate the performance of metagenomic next-generation sequencing (mNGS) in identifying microbiological etiologies in pediatric patients with hematological malignancies undergoing fever of unknown origin (FUO).A total of 147 children with hematological malignancy suffering febrile diseases without definite microbiological etiologies under conventional tests were enrolled. The clinical record, serum inflammatory biomarkers and mNGS results were analyzed.At least one microorganism was identified by mNGS in 112 of 147 patients (76.2 %). Two or more types of organisms were detected simultaneously in 35.7 % (40/112) of samples. Of the 112 cases with positive mNGS results, the reported microorganisms were considered as etiologies of fever in 50 (44.6 %) cases. The initial antimicrobial regimens were adjusted according to the mNGS results in 48 cases, with 41 patients' febrile diseases resolved. Totally, 27.9 % (41/147) of patients benefit from mNGS. High IL-6 (390 pg/mL) level was associated with bacterial infection and could help to interpret the results of mNGS.mNGS is a novel approach to determine the microbiological etiology of FUO in hematological malignancy patients, which benefits about a quarter of all patients tested. Integration of IL-6 can improve the diagnostic precision of bacterial infection.

Patients meeting the criteria for fever of unknown origin (FUO) can be evaluated with structured or nonstructured approaches, but the optimal diagnostic method is unresolved.To analyze differences in diagnostic outcomes among patients undergoing structured or nonstructured diagnostic methods applied to prospective clinical studies.PubMed, Embase, Scopus, and Web of Science databases with librarian-generated query strings for FUO, PUO, fever or pyrexia of unknown origin, clinical trial, and prospective studies identified from January 1, 1997, to March 31, 2021.Prospective studies meeting any adult FUO definition were included. Articles were excluded if patients did not precisely fit any existing adult FUO definition or studies were not classified as prospective.Abstracted data included years of publication and study period, country, setting (eg, university vs community hospital), defining criteria and category outcome, structured or nonstructured diagnostic protocol evaluation, sex, temperature threshold and measurement, duration of fever and hospitalization before final diagnoses, and contribution of potential diagnostic clues, biochemical and immunological serologic studies, microbiology cultures, histologic analysis, and imaging studies. Structured protocols compared with nonstructured diagnostic methods were analyzed using regression models.Overall diagnostic yield was the primary outcome.Among the 19 prospective trials with 2627 unique patients included in the analysis (range of patient ages, 10-94 years; 21.0%-55.3% female), diagnoses among FUO series varied across and within World Health Organization (WHO) geographic regions. Use of a structured diagnostic protocol was not significantly associated with higher odds of yielding a diagnosis compared with nonstructured protocols in aggregate (odds ratio [OR], 0.98; 95% CI, 0.65-1.49) or between Western Europe (Belgium, France, the Netherlands, and Spain) (OR, 0.95; 95% CI, 0.49-1.86) and Eastern Europe (Turkey and Romania) (OR, 0.83; 95% CI, 0.41-1.69). Despite the limited number of studies in some regions, analyses based on the 6 WHO geographic areas found differences in the diagnostic yield. Western European studies had the lowest percentage of achieving a diagnosis. Southeast Asia led with infections at 49.0%. Noninfectious inflammatory conditions were most prevalent in the Western Pacific region (34.0%), whereas the Eastern Mediterranean region had the highest proportion of oncologic explanations (24.0%).In this systematic review and meta-analysis, diagnostic yield varied among WHO regions. Available evidence from prospective studies did not support that structured diagnostic protocols had a significantly better rate of achieving a diagnosis than nonstructured protocols. Clinicians worldwide should incorporate geographical disease prevalence in their evaluation of patients with FUO.

A 59-year-old man presented to the emergency department with fever and chills that began 6 weeks earlier, when a symptomatic deep vein thrombosis (DVT) of the right posterior tibial vein had been diagnosed. The patient had also noticed word-finding difficulties and mild headache for the week before

Objective To describe a group of patients with suspected acute invasive fungal rhinosinusitis (AIFRS) diagnosis, and identify factors associated with a greater risk of presenting this disease. Design Non-concurrent cohort study. Setting A single-centre non-concurrent follow-up of patients with suspected AIFRS between August 2015 and July 2018. Participants 50 inpatients referred due to suspected AIFRS at Hospital Clinico Universidad Catolica based on the association of a predisposing factor (neutropenia/immunodeficiency/poorly controlled diabetes) with fever of unknown origin. Main outcome measure The primary outcome was AIFRS diagnosis, defined as a concordant tissue biopsy. Results Acute invasive fungal rhinosinusitis was confirmed in 18% (9/50) of the evaluated patients. AIFRS was significantly associated with a positive galactomannan (P = .04), and a paranasal sinus MRI with lack of contrast enhancement (LoCE) (P = .04) orbit compromise (P = .03) or global extrasinusal extension (P = .04). LoCE and extrasinusal extension in the paranasal sinus/brain MRI were risk factors for AIFRS (OR 16; CI 1.2-210.6 and OR 12.75; CI 1.3-128.8, respectively). Conversely, a nasal endoscopy showing healthy mucosa was identified as a protective factor for AIFRS (OR 0.06; CI 0.007-0.57). Conclusions In patients with suspected AIFRS, we identified laboratory and radiologic variables associated with the disease, which may help for a more accurate diagnostic algorithm and approach in this population.

The diagnosis of visceral leishmaniasis (VL) is complicated and often unsuspected. Little is known of the usefulness of nuclear imaging in VL. Our objective was to describe findings seen in fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in cases of VL. We retrospectively reviewed VL cases diagnosed at Vall d’Hebron University Hospital from May 2012 to May 2018 and selected those that had an FDG-PET/CT performed. Information on procedures and details of the FDG-PET/CT features and follow-up were collected. We then systematically reviewed the literature on VL and FDG-PET/CT. Four of 43 patients diagnosed with VL had an FDG-PET/CT performed. All four patients presented diffuse splenic uptake of FDG-PET/CT. Adenopathy was not always present, and bone marrow uptake was found in two patients. A posttreatment FDG-PET/CT in one patient revealed normalization of initial findings. In the literature review, 43 of 50 cases presented similar splenic uptake in the PET/CT, being described as different patterns: “increased metabolism,” “homogeneous,” “diffuse,” “diffuse and multifocal,” “nodular,” “patchy and granular,” “subcortical,” and “compatible with lymphoma.” Other frequent findings were bone marrow uptake and adenopathies. We, therefore, conclude that FDG-PET/CT could become a useful tool for the diagnosis and follow-up of VL and that VL should be taken into account in patients with fever of unknown origin with enhanced splenic uptake in FDG-PET/CT. Differential diagnosis in these cases should be made with splenic primary lymphoma, virus infections, chemotherapy, and colony-stimulating factor therapy. Further structured studies with more cases are needed to define its diagnostic and prognostic value.

Objectives The aim of this study was to evaluate the characteristics of fever of unknown origin (FUO) according to the definition with qualitative study criterion and of patients without diagnosis. Materials and methods Prospective observational study performed from 2009 to 2017 of all patients who were diagnosed with FUO according to the extended definition with qualitative study criterion. Demographic, clinical, diagnostic and evolving variables were evaluated. Results Of the 87 patients registered, 17.3% presented criteria of inflammation of unknown origin (IUO). The diagnoses were: non-infectious inflammatory diseases (NIID) in 19 patients (21.8%), infections in 15 (17.2%), miscellaneous in 14 (16.1%), malignant diseases in 13 (15%) and without diagnosis in 26 (29.9%). In 17.6% of the cases, a potentially diagnostic clue (PDC) was identified. The patients without diagnosis were characterized by a lower number of total PDC (5.9 ± 3.3 vs. 8.7 ± 3.4; P = .000), fewer clinical signs (.4 ± .6 vs. .9 ± .8; P = .001), a smaller number of tests in the previous study (2.7 ± 2.1 vs. 4.6 ± 2; P = .000), a shorter diagnostic interval (14.6 ± 7.7 days vs. 21.4 ± 9.5 days; P = .029) and less alteration of erythrocyte sedimentation rate (52.3 ± 41.3 mm/h vs. 89.8 ± 42.7 mm/h; P = .000), haemoglobin (12.9 ± 1.7 g/dl vs. 11.7 ± 1.6 g/dl; P = .003) and albumin (36.9 ± 6.4 g/l vs. 33.2 ± 7.2 g/l; P = .025). 18F-fluorodeoxyglucose positron-emission tomography combined with computed tomography (18F-FDG-PET/TC) proved to be helpful in 37% of the cases. Mortality was 6.8%. Conclusions The definition of FUO with qualitative study criterion incorporates a diagnostic protocol that provides clear benefits in terms of cost-effectiveness.

We report, to the best of our best knowledge, the oldest individual to ever be diagnosed with Familial Hemophagocytic Lymphohistiocytosis (FHL) Type 2 from homozygous c.1349C>T (p.T450M) missense variants in the PRF1 gene. This rare case advanced in complexity with a simultaneous diagnosis of Chronic Active Epstein-Barr Virus (CAEBV) - a distinct clinical entity from acute EBV infections and a well-described trigger of Hemophagocytic Lymphohistiocytosis (HLH). This is, to the best of our knowledge, the only individual to ever be diagnosed with CAEBV in the setting of this specific variant and the oldest to be diagnosed with a coexisting perforin variant. This case provides understanding of EBV, human genetics, and lymphoproliferative disorders while adding a unique differential diagnosis to adults who present with fever of unknown origin and diffuse lymphadenopathy without evidence of malignancy. This report explores the diagnosis and treatment of both HLH and CAEBV, encouraging discussion regarding current clinical management and future research needs.

Imaging of musculoskeletal disorders, including arthritis, infection, osteoporosis, sarcopenia, and malignancies, is often limited when using conventional modalities such as radiography, computed tomography (CT), and MR imaging. As a result of recent advances in Positron Emission Tomography (PET) instrumentation, total-body PET/CT offers a longer axial field-of-view, higher geometric sensitivity, and higher spatial resolution compared with standard PET systems. This article discusses the potential applications of total-body PET/CT imaging in the assessment of musculoskeletal disorders.

Leishmaniasis is a vector-born parasitic disease characterized by predominant cutaneous or visceral involvement with fever, hepatosplenomegaly and anemia. Leishmaniasis has relatively high prevalence in tropical and subtropical areas. Several sporadic and mostly imported cases are detected in Russian Federation. Nevertheless, some local incidents are noted in southern areas (Crimea, Dagestan). Lack of epidemiological alertness hampers confirmation of diagnosis and may lead to incorrect treatment. The article summarizes current state of knowledge in epidemiology, diagnostic approach and treatment of leishmaniasis. Particular clinical case is discussed.Лейшманиозы протозойные трансмиссивные заболевания, характеризующиеся преимущественным поражением внутренних органов (висцеральные лейшманиозы) или кожи (кожные лейшманиозы) с развитием лихорадки, спленомегалии и анемии. В Российской Федерации большинство зафиксированных случаев связано с посещением стран, эндемичных по лейшманиозу; в то же время имеются единичные сообщения о развитии заболевания у лиц, посетивших южные регионы России (Крым, Дагестан) и Закавказье или постоянно проживающих в них. Отсутствие настороженности со стороны клиницистов существенно затрудняет своевременную постановку правильного диагноза и может привести к выбору неверной тактики лечения. В статье рассмотрены современные представления об эпидемиологии, подходах к диагностике и лечению лейшманиоза; обсуждаются особенности представленного клинического случая.

Background Bloodstream infection (BSI) is a significant cause of mortality among patients with fever of unknown origin (FUO). Inappropriate empiric antimicrobial therapy increases difficulty in BSI diagnosis and treatment. Knowing the risk of BSI at early stage may help improve clinical outcomes and reduce antibiotic overuse. Methods We constructed a multivariate prediction model based on clinical features and serum inflammatory markers using a cohort of FUO patients over a 5-year period by Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression. Results Among 712 FUO patients, BSI was confirmed in 55 patients. Five independent predictors available within 24 h after admission for BSI were identified: presence of diabetes mellitus, chills, C-reactive protein level of 50–100 mg/L, procalcitonin > 0.3 ng/mL, neutrophil percentage > 75%. A predictive score incorporating these 5 variables has adequate concordance with an area under the curve of 0.85. The model showed low positive predictive value (22.6%), but excellent negative predictive value (97.4%) for predicting the risk of BSI. The risk of BSI reduced to 2.0% in FUO patients if score Conclusions A simple tool based on 5 variables is useful for timely ruling out the individuals at low risk of BSI in FUO population.

ObjectiveTo evaluate the impact of introducing the Step-by-Step approach on care quality in young febrile infants.DesignObservational study including infants ≤90 days old with fever without source seen in a paediatric emergency department 5 years before (n=1222) and after (n=1151) its introduction. Quality of care was evaluated in terms of adherence to recommendations, resource use and safety.ResultsAdherence: percentages of infants undergoing both urine and blood tests and infants ConclusionThe introduction of the Step-by-Step increased the quality of care provided to young febrile infants.

Background Infectious disease is the leading cause of fever of unknown origin (FUO). Serum inflammatory markers historically used to diagnose bacterial infection have sufficient diagnostic sensitivity but low specificity. This study aimed to develop a simple scoring system for differentiating bacterial infections from other causes of early-stage FUO. Methods This study included a retrospective cohort of patients presenting with FUO at the Huashan Hospital (January 2014 to June 2017). The diagnostic utility of serum inflammatory markers for bacterial infection was evaluated using the receiver operating characteristic (ROC) curve analysis. Relevant markers were subsequently measured prospectively in a separate cohort of FUO patients (December 2017 to May 2019). A scoring system was based on inflammatory markers and other test results. Results Bacterial infection was identified in 34% of patients in the retrospective cohort. The area under the ROC curve (AUC) was 0.644 (95% confidence interval [CI], .595–.693) for C-reactive protein, 0.624 (95% CI, .573–.675) for procalcitonin, and 0.646 (95% CI, .595–.697) for serum ferritin (SF) in diagnosing bacterial infection. Bacterial infection was found in 29% of cases in the prospective cohort. A model based on serum amyloid A (SAA) and SF levels and neutrophil percentage yielded an AUC of 0.775 (95% CI, .695–.854). Validation analysis indicated lower probability ( Conclusions A scoring system based on SAA and SF levels and neutrophil percentage can help distinguish bacterial infection from other causes of FUO, potentially reducing antibiotic use.

Cat scratch disease (CSD) is the main clinical manifestation caused by Bartonella henselae in immuno-competent patients. The bacterium is transmitted to humans from cats via scratches or bites. In this case report, we are presenting to our knowledge the first etiologically confirmed case of CSD in our country. Here we describe the case of a previously healthy adult female patient presenting with fever and axillar lymphadenopathy over 1-month period. She underwent numerous clinical and paraclinical investigations for potential etiologies associated with lymphadenopathy and fever. Finally, serological testing for B.henselae was performed with titers for IgG 1:1024 and 1:160 for IgM, which confirmed the diagnosis. Five-day treatment with azithromycin resulted with good clinical response and complete recovery. We proved that CSD is a reality in our country and this report should raise awareness in medical doctors, especially infectious disease specialist. Also, CSD should be included in differential diagnosis in patients with fever of unkown origin (FUO), who are presenting with regional lymphadenopathy, with or without history of cat contact.