Etiologic Agents of Fever of Unknown Origin Among Patients Attending Mnazi Mmoja Hospital, Zanzibar.

BACKGROUND: Fever of unknown origin (FUO) remains an important public health problem. With malaria transmission declining in some parts of Africa, the evidence suggests other infectious agents now account for most FUO. The purpose of this study was to identify the etiologic agents of FUO in a cross-section of patients at the Mnazi Mmoja hospital in Zanzibar, Tanzania. METHODOLOGY: A multiplex TaqMan gene expression Array Card (TAC) and plates were used for detection and classification of different pathogens in blood samples obtained from patients with FUO. Logistic regression analyses was performed using pathogens detected and sociodemographic characteristics as outcome and exposure variables respectively. Odd ratios and 95% confidence interval were calculated and statistical significance was set at P < .05. RESULT: Thirty-three different pathogens were detected in 27 patient blood samples. The following pathogens were detected in decreasing order of prevalence; Dengue virus, Plasmodium species, Rickettsia, Brucella species, Salmonella typhi, and less than 1% for each of Bartonella, Coxiella burnetii, Salmonella species, and Leptospira. Co-infections of Plasmodium with Dengue and S. typhi were also detected, including one case with three different pathogens-Plasmodium, Rickettsia and Brucella. There was no association between the etiologic agents of FUO and demographic or clinical characteristics. CONCLUSIONS: Zoonotic and arboviral etiological agents of fever of unknown origin are present among patients at the Mnazi Mmoja hospital in Zanzibar, Tanzania. There is a need to develop a baseline of standardized diagnostic approaches particularly within the hospital setting. In areas with low malaria prevalence like Zanzibar, Dengue, Rickettsia, Coxiella burnetii, Brucellosis should be considered by clinicians in the differential diagnoses of FUO.

18F-FDGPET/CT in fever of unknown origin and inflammation of unknown origin: a Chinese multi-center study.

PURPOSE: To evaluate the clinical value of 18F-FDG-PET/CT for the diagnosis of fever of unknown origin (FUO) and inflammation of unknown origin (IUO) in Chinese population, as well as the characteristics of PET/CT in different category of etiological disease. METHODS: A total of 376 consecutive patients with FUO/IUO who underwent FDG-PET/CT at 12 hospitals were retrospectively studied. FDG uptake was quantitatively and visually evaluated, by using SUVmax and a 4-grade scale respectively. A questionnaire survey to the clinicians was used to evaluate the significance of PET/CT in diagnosing of FUO/IUO. Data analysis included the etiological distribution in the study population, image characteristics in different category of diseases, and clinical significance of PET/CT. RESULTS: In 376 studied patients, the infectious diseases accounted for 33.0% of patients, rheumatologic diseases for 32.4%, malignancies for 19.1%, miscellaneous causes for 6.6%, and cause unknown for 8.8%. However, the etiological distribution among hospitals was varied. In addition, the etiological disease composition ratio has changed over time in China. On PET/CT examinations, 358 (95.2%) of the patients had a positive finding. Within them, local high uptake lesion was found in 219 cases, and nonspecific abnormal uptake (NAU) was found in 187 cases. FDG uptake in malignant diseases was significantly higher than in other category diseases both on SUVmax and visual scores (t-value range from 4.098 to 5.612, all P value < 0.001). Based on a clinical questionnaire survey, PET/CT provided additional diagnostic information for 77.4% of patients, and 89.6% of patients benefited from PET/CT examination. CONCLUSIONS: FDG PET/CT is a valuable tool for clinical diagnosis of FUO/IUO, and it is of great significance in further investigating the usefulness of PET/CT in non-neoplastic diseases.

Characteristics of Functional Hyperthermia Detected in an Outpatient Clinic for Fever of Unknown Origin.

Background: Functional hyperthermia (FH) is characterized by hyperthermia resulting from sympathetic hyperactivity rather than inflammation, and it is frequently overlooked by medical practitioners due to the absence of abnormalities in a medical examination. Although FH is an important differential diagnosis for fever of unknown origin (FUO), the literature on FUO cases in Japan lacks information on FH. In this study, we aimed to uncover the population of FH patients hidden in FUO cases. Methods: An outpatient clinic for FUO was established at Okayama University Hospital, and 132 patients were examined during the period from May 2019 to February 2022. Results: A diagnosis of FH was made in 31.1% of the FUO cases, and FH predominantly affected individuals in their third and fourth decades of life with a higher incidence in females (68.3%). The frequency of a history of psychiatric illness was higher in patients with FH than in patients with other febrile illnesses. Although the C-reactive protein (CRP) is generally negative in FH cases, some obese patients, with a body mass index ≥ 25 had slightly elevated levels of CRP but were diagnosed with FH. Conclusions: The results showed the importance of identifying FH when encountering patients with FUO without any organic etiology.

[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.

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.

A Rare Case of Amyloidoma of the Chest Wall Presented with Fever of Unknown Origin.

Amyloidoma of the chest wall is an uncommon entity, consisting of a solitary tumor-like deposit of amyloid. Until now, while rarely reported, it was mostly presented with back pain and swelling. Here, we report the first case of a chest wall amyloidoma initially presented with fever of unknown origin. Due to the rarity of the lesion as a primary entity, protein electrophoresis and long-term follow-up are required. In addition, patients undergoing long-term hemodialysis are particularly at risk for such acquired amyloidosis. However, soft-tissue tumors, considered as amyloidoma, is also rare in patients with long-term hemodialysis. For patients with a fever of unknown primary origin, clinicians should keep amyloidoma in mind, especially in high-risk populations.

Giant Hepatic Hemangioma Causing Prolonged Fever and Indicated for Resection.

Hepatic hemangiomas are benign liver tumors, and most of them progress asymptomatically. We report a case of hepatic hemangioma considered the cause of fever. A 53-year-old woman had a fever of 40°C for about 3 months without infection. Hepatic hemangiomas with internal bleeding of 10 cm in size on liver S8/7 and S3/2 were observed. These were resected laparoscopically for diagnostic treatment. She was afebrile after the operation. The pathological diagnosis was hematoma inside cavernous hemangioma. It should be noted that a bleeding hepatic hemangioma may cause fever of unknown origin and be indicated for resection.

Giant Cell Arteritis among Fevers of Unknown Origin (FUO): An Atypical Presentation.

Giant cell arteritis (GCA), or Horton's arteritis, presenting solely as fever is very rare. Usually, it manifests with typical features such as visual problems, headache and jaw claudication, or it can be associated with polymyalgia rheumatica. We describe the case of a patient with GCA who presented only with prolonged fever, the cause of which was not determined by diagnostic tests. LEARNING POINTS: Fever may be the only symptom of giant cell arteritis (GCA).It is important to consider GCA in the differential diagnosis of fever of unknown origin as early diagnosis is crucial for prompt treatment and to prevent catastrophic complications such as vision loss or stroke.Temporal artery biopsy remains the gold standard for diagnosing GCA.

Retrospective analysis of 1,641 cases of classic fever of unknown origin.

BACKGROUND: Fever of unknown origin (FUO) is commonly defined as fever higher than 38.3 °C on several occasions during at least 3 weeks with uncertain diagnosis after a number of obligatory investigations. It is a special type of fever and a common disease in internal medicine. However, due to its complex etiology, lack of characteristic clinical manifestations, and insufficient laboratory examination indicators, it often baffles clinicians in diagnosis. We herein present a study of the etiological factors and clinical features of classic fever of unknown origin (FUO) to provide help for related clinical diagnosis and treatment. METHODS: A total of 1,641 cases of patients with classic FUO hospitalized in West China Hospital of Sichuan University between January 1, 2011 and December 31, 2017, were collected, and the etiological factors of classic FUO were analyzed. A special effort was made to explore and screen the laboratory indicators related to infectious diseases, and the above data were compared with the clinical features of tuberculosis and lymphoma, which are difficult to diagnose. RESULTS: Among the 1,641 patients, 1,504 were finally diagnosed through various types of examination or diagnostic methods, and the diagnosis rate was 91.65%. Among all the causes of the 1,641 cases of FUO, 48.69% [799] were infectious diseases, of which tuberculosis was the most common, accounting for 19.50% [320]. Connective tissue diseases were responsible for 19.26% [316] of cases, of which adult-onset Still's disease (AOSD) was the most common, comprising 89 (5.42%) of the cases; 16.94% [278] were neoplastic diseases, and lymphoma (143, 8.71%) cases, was the most common malignant tumor; 6.76% [111] were other diseases; and in 8.35% [137] of cases, the cause was unclear. Through comparative analysis of tuberculosis and lymphoma, no significant differences were found between the symptoms, signs, and non-specific routine examination results of the two diseases. The diagnosis of these diseases was more dependent on tuberculosis-related examinations and pathological examinations. CONCLUSIONS: Infectious diseases are the principal cause of classic FUO, in which tuberculosis accounts for a large proportion. Non-infectious diseases that cause FUO are mainly connective tissue diseases and malignant tumors. Of the various causes of classic FUO, tuberculosis and lymphoma are relatively difficult to diagnose. In most cases, the causes of classic FUO can be ascertained.

Long-term Health Outcomes of Patients Evaluated for Unexplained Fever in a Pediatric Infectious Diseases Clinic.

A telephone interview was conducted with parents of 120 children seen in a pediatric infectious diseases clinic for unexplained fever who received no definitive diagnosis or were thought to have recurrent self-limited illnesses. Only 3 were diagnosed with a fever-related condition after 8 years of follow-up. The majority remained well.

Intravascular Large B-cell Lymphoma: A Report of Two Cases.

One of the rare variants of extranodal large B-cell lymphoma is intravascular large B-cell lymphoma (IVLBCL). Characteristics of IVLBCL include intraluminal selective proliferation of atypical lymphoid cells in small to medium-sized vessels. The etiologic of IVLBCL is unknown, but due to the growth pattern of this tumor, it is speculated that IVLBCL is caused by a defect in homing receptor of tumor cells. IVLBCL can involve any organ but central nervous system, lungs, and skin are the most involved sites. IVLBCL does not usually involve lymph nodes. IVLBCL mainly occurs in the middle aged to elderly population with a slight male predominance. Generally, IVLBCL is aggressive and rapidly fatal if left untreated. We here reported two cases of IVLBCL who succumbed to the disease at initial phase of treatment to emphasize the difficulty in diagnosis of IVLBCL due to its exclusive intravascular growth pattern and fulminant clinical course.

Adult-onset Still's disease accompanying noninfective endocarditis.

Adult-onset Still's disease can develop valve lesions. Since AOSD may complicate valvular lesion, differentiation of endocarditis in patients with AOSD is required.

Combined clinical parameters improve the diagnostic efficacy of 18F-FDG PET/CT in patients with fever of unknown origin (FUO) and inflammation of unknown origin (IUO): A prospective study in China.

OBJECTIVES: To improve the diagnostic efficacy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for Chinese patients with fever of unknown origin (FUO) and inflammation of unknown origin (IUO), with combined clinical parameters. MATERIALS AND METHODS: FUO/IUO patients who underwent a standard diagnostic work-up and 18F-FDG PET/CT scanning were enrolled and divided into a local uptake lesion subgroup and a non-specific abnormal uptake subgroup. Beneficial clinical parameters for improving the diagnostic efficacy of PET/CT were identified. RESULTS: From January 2014 to January 2019, 253 FUO/IUO patients were studied. In total, 147 patients had local uptake lesions and 106 patients had non-specific abnormal uptake. In the local uptake lesion group, the positioning accuracy of PET/CT was 37.2% in grades 1 and 2, and 66.3% in grades 3 and 4. With the following combination of clinical parameters, the positioning accuracy increased to 75.0% and 90.0%, respectively: time from admission to performing PET/CT scanning <6.5 days and C-reactive protein level >95 mg/l. In the non-specific abnormal uptake group, the combination of sex (male), bicytopenia, and lactic dehydrogenase improved the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for diagnosing malignancy from 64.3%, 69%, 60%, and 72.7%, respectively, to 83.3%, 81%, 81.4%, and 82.9%, respectively. With the combination of sex (male), white blood count, serum ferritin level, and hepatosplenomegaly, the infection prediction model had a sensitivity, specificity, PPV, and NPV of 78%, 76.2%, 76.6%, and 77.6%, respectively. CONCLUSIONS: Combined clinical parameters improved the localization diagnostic value of 18F-FDG PET/CT in the local uptake lesion subgroup and the etiological diagnostic value in the non-specific abnormal uptake subgroup.

Fever of unknown origin and Q-fever: a case series in a Bulgarian hospital.

BACKGROUND: Fever of unknown origin (FUO) is a perplexing medical problem. The causes for FUO are more than 200 diseases. The aim of the study was to present human clinical cases of Coxiella burnetii infection debuting as FUO. METHODS: The following methods were conducted in the study: literature search, laboratory, imaging, and statistical methods. Criteria of Durack and Street were applied for FUO definition. For the etiological diagnosis indirect immunoenzyme assay (ELISA) for antibodies detection against Coxiella burnetii was used (cut-off = 0.481-0.519). RESULTS: From 2008 until 2015, nine patients with FUO caused by C. burnetii were hospitalized at the Military Medical Academy of Sofia. Male gender was predominant (male/female - 77.8% /22.2%), mean age was 48.78±14.52 years (range: 26-67), hospital stay was 9.78±2.95 days (range: 5-15), fever duration was 54.33±56.23 days (range: 21-180). Laboratory investigations estimated the elevation of erythrocyte sedimentation rate 49.11±31.74mm/h (95%CI = 13.09-111.31), C-reactive protein 37.68±37.62mg/L (95% CI = 36.07-111.42) and fibrinogen 5.69±1.59g/L (95% CI=2.57-8.81). The mean values of liver enzymes were in reference range. Among imaging tests, abdominal ultrasound and X-ray demonstrated 33.3% contribution to the final diagnosis. Transthoracic echocardiography found 22.2% contribution. Serological methods presented 100% contribution. CONCLUSION: C. burnetii infection was accepted as a final diagnosis among 9 patients with FUO based on the integrated information from the applied methods. Active search and establishment of this pathogen among FUO should lead to avoiding potential complications and consequences in case of untreated patients infected with C. burnetii.

Undifferentiated epithelioid sarcoma presenting as a fever of unknown origin: a case report.

BACKGROUND: Fever of unknown origin is often a diagnostic dilemma for clinicians due to its extremely broad differential. One of the rarer categories of disease causing fever of unknown origin is malignancies; of these, soft tissue sarcoma is one of the least common. Soft tissue sarcomas make up < 1% of all adult malignancies and often do not present with any systemic manifestations or neoplastic fevers. CASE PRESENTATION: A 73-year-old Caucasian woman presented with a 2-week history of fever and profound fatigue. The only other symptom she endorsed was a transient history of left knee pain, initially thought to be unrelated. There was no clear cause on initial examination and routine investigations, but her C-reactive protein was significantly elevated at 207 mg/L. Blood cultures and a urine culture were drawn. She was admitted to hospital for further investigation and placed on empiric antibiotics. Her blood cultures were negative, but she had one further fever in hospital. Computed tomography scans did not yield a cause of her fever. No vegetations were seen on echocardiography. Antibiotics were stopped as she did not seem to have an acute infectious cause of her fever. No new symptoms developed. She felt well enough to proceed with out-patient follow up and was discharged after 8 days in hospital. At 1-month post-discharge: no resolution of symptoms, but she endorsed a recurrence of her left knee pain. Ultrasound and magnetic resonance imaging revealed a 4.5 × 6.8 × 11.6 cm soft tissue mass, identified as a sarcoma on biopsy. She subsequently underwent a distal femur resection. Final staging was pT2bN0M0. She underwent adjuvant radiation therapy, but was found to have developed metastatic disease. CONCLUSION: This case revealed an atypical presentation of a rare soft tissue sarcoma as the cause of the illness. The etiology behind a fever of unknown origin can be difficult to elucidate, making the approach to investigation particularly important. Repeated history-taking and serial physical examinations can be crucial in guiding investigations and ultimately arriving at a diagnosis. In addition, we believe this case highlights the adage that no seemingly innocuous symptom should be left out when working up a condition with such an extensive and complex differential.

Atypical familial Mediterranean fever developed in a long-term hemodialysis patient.

Familial Mediterranean Fever (FMF) is usually an autosomal recessive autoinflammatory disease characterized by recurrent attacks of fever and serositis. FMF develops before the age of 20 years in 90% of patients. It has intervals of 1 week to several years between attacks, which leads to renal dysfunction-amyloidosis. We report a case of atypical FMF that developed in a long-term hemodialysis patient. A 65-year-old Japanese female undergoing hemodialysis for 32 years was referred to our hospital with a fever of unknown origin (FUO) following cervical laminoplasty. The fever occurred as recurrent attacks accompanied by oligoarthralgia of the left hip and knee. We suspected FMF because of recurrent self-limited febrile attacks, although the patient showed atypical clinical features such as late-onset and highly frequent attacks. After receiving treatment, she achieved a complete response to colchicine. Therefore, a diagnosis of FMF was made based on the Tel-Hashomer criteria, which was confirmed by genetic testing. The case suggests that FMF may be of note in long-term hemodialysis patients developing FUO.

Do clinical and laboratory variables have any impact on the diagnostic performance of 18F-FDG PET/CT in patients with fever of unknown origin?

OBJECTIVE: To assess the influence of clinical features and laboratory test results on the determination of fever of unknown origin (FUO) by means of 18F-FDG PET/CT. METHODS: Retrospective and longitudinal analysis, including all the PET/CT studies requested for FUO. Reference standard was established by serology, cultures or biopsy with other laboratory tests or clinical follow-up when necessary. Clinical variables, inflammation markers, protein analysis, serology and culture results close to the PET scan were obtained. The final diagnosis was classified into three groups attending to the etiology; group 1: infection or neoplasm, group 2: vasculitis, autoimmune disease or non-infectious inflammatory disease and group 3: auto-limited fever or persistent fever without diagnosis. PET/CT scans were classified as positive or negative and helpful or not in the diagnosis of the fever origin. The effect of clinical features and laboratory variables on the PET/CT results was analyzed. RESULTS: Sixty-seven patients were evaluated. The final diagnosis was: Group 1 (25), Group 2 (20) and Group 3 (22). 89.6% of patients had a positive inflammation marker, 28.4% proteinogram alterations and 20.9% positive cultures. PET/CT was positive in 52/67 patients. PET/CT helped in the establishment of the fever origin in 35 cases and was especially helpful in groups 1 and 2. Sensitivity, specificity and accuracy of PET/CT were: 84, 31 and 61%. PET results shown significant relations with the final diagnosis (p = 0.035) and culture results (p = 0.037). No significant relations were observed with the rest of clinical or laboratory variables. CONCLUSIONS: 18F-FDG PET/CT had a high sensitivity but a low specificity in the diagnosis of the fever origin, probably due to the high rate of diffuse and auto-limited aetiologies. Patients who are most likely to benefit from the PET/CT study would be those with several positive inflammation markers, reflecting a higher pre-test probability of active disease.

Diagnostic contribution of (18)F-FDG-PET/CT in fever of unknown origin.

OBJECTIVES: Fever of unknown origin (FUO) remains one of the most compelling diagnostic issues in medicine. We aimed to evaluate the potential clinical contribution of 18-fluoro-2-deoxyglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) in the identification of the underlying cause of FUO. METHODS: Fifty consecutive patients (27 men and 23 women; age range 16-88 years) with FUO based on the revised definition criteria were included in the study. A diagnostic protocol including biochemistry, histopathology, and microbiological tests was performed and the patients were followed up. FDG-PET was performed in 25 of the 50 patients (12 males and 13 females; age range 16-88 years) in order to determine the etiology of the patient's fever. PET-CT images were obtained with the Gemini Philips TF (18)F-FDG-PET/CT camera after a 60-min 'standard uptake' period following an injection of a mean 330 MBq (range 290-370 MBq) intravenous (18)F-FDG. RESULTS: A total of 21 patients were available for analysis of the diagnostic contribution of PET/CT (two patients were undiagnosed and two had non-contributory PET/CT findings). (18)F-FDG-PET/CT was able to precisely detect the cause of fever in 60% of the cases (n=15). The accuracy, sensitivity, and specificity of this imaging modality were 90.5%, 93.8%, and 80%, respectively. Among the cases with a true-positive (18)F-FDG-PET/CT finding (i.e., 15 cases), the identified underlying causes of FUO included localized infection (n=7), non-infective inflammatory process (n=5), and malignancy (n=3). CONCLUSIONS: Further studies to confirm the high diagnostic yield of (18)F-FDG-PET/CT observed in the present study would lend support to the inclusion of this imaging modality in the initial diagnostic work-up of patients with suspected FUO.

Changing pattern of infectious etiology of fever of unknown origin (FUO) in adult patients in Ahvaz, Iran.

BACKGROUND: Although infectious diseases are the most common sources for the fever of unknown origin (FUO), but the spectrum of infectious diseases is changing overtime. The purpose of the study was to define the clinical spectrum and changing the pattern of FUO. METHODS: This existing data based study was undertaken from 2007 to 2011. One hundred-six patients fulfilling the modified criteria for FUO referred in a teaching hospital in Ahvaz were enrolled for analysis. The data extracted from the patient's medical files and etiologic agents caused FUO to be assessed. RESULTS: Infections were the most common cause of FUO in 48.4% of the patients. Among the infections, the most important causes of FUO were represented by extra-pulmonary tuberculosis 15 (31.9%), osteomyelitis 10 (21.3%) and abdominal abscesses 6 (12.8%). CONCLUSION: The pattern of FUO in the region is thought to be changed to extra pulmonary TB and osteomyelitis. Tuberculosis is still the leading cause of FUO in our region.