Causes Of Fever Of Unknown Origin Research Articles

Fever of unknown origin (FUO) due to large B-cell lymphoma: The diagnostic significance of highly elevated alkaline phosphatase and serum ferritin levels

BackgroundDetermining the cause of fever of unknown origin (FUO) is often a vexing and difficult diagnostic process. In most cases, the signs and symptoms in adult FUOs suggest a malignant, infectious, or rheumatic/inflammatory etiology. The diagnosis of FUO may be narrowed if specific findings are present (eg, hepatosplenomegaly) that limit the diagnostic possibilities. Infectious causes of FUO with hepatosplenomegaly include miliary tuberculosis, typhoid fever, and visceral leishmanosis (kala-azar). However, FUOs with hepatosplenomegaly are most often attributable to malignant neoplasms, ie, Hodgkin lymphoma, non-Hodgkin lymphoma, hepatoma, hypernephroma (renal-cell carcinoma), or preleukemia. Methods and ResultsWe present a middle-aged woman with FUO and hepatosplenomegaly. Inpatient nonspecific laboratory findings included a highly elevated erythrocyte sedimentation rate, and elevated levels of vitamin B12, lactate dehydrogenase, angiotensin-converting enzyme, ferritin, and alkaline phosphatase. These individual findings are nonspecific, but together point to a lymphoma. An important test in differentiating malignant from infectious FUOs is the Naprosyn test, and her Naprosyn test was positive, indicating malignancy. A gallium scan suggested a uterine lymphoma. A computed tomography scan revealed hepatosplenomegaly, but the gallium uptake was not increased in her liver and spleen. Uterine and bone marrow biopsies were negative for lymphoma. ConclusionWe present a case of FUO with hepatosplenomegaly attributable to large B-cell lymphoma as diagnosed via liver biopsy.

Fever of unknown origin (FUO) in an elderly adult due to Epstein-Barr virus (EBV) presenting as “typhoidal mononucleosis,” mimicking a lymphoma

We describe fever of unknown origin (FUO) in a 57-year-old woman with hepatosplenomegaly. The diagnostic workup was directed at diagnosing a lymphoma. Her history of travel and exposures to food and water did not make typhoid fever a likely diagnostic possibility. Because she presented with prolonged fevers, fatigue, anorexia, weight loss, and night sweats with hepatosplenomegaly, lymphoma was likely. Initially, Epstein-Barr virus (EBV) was not considered because of her age, the absence of pharyngitis and cervical adenopathy, and the higher likelihood of another diagnosis, ie, lymphoma. Eventually, her FUO was diagnosed as EBV presenting as “typhoidal mononucleosis.” Typhoidal mononucleosis is an extremely rare presentation of EBV as a cause of FUO in an adult. All of her symptoms as well as her clinical and laboratory findings resolved spontaneously.

Spectrum of 18F-FDG PET/CT Findings in Patients Presenting With Fever of Unknown Origin

The objective of this article is to provide an illustrative tutorial highlighting the clinical utility of (18)F-FDG PET/CT for imaging patients presenting with fever of unknown origin (FUO). FDG PET/CT is a powerful tool in localizing an inciting source in patients with FUO. The high sensitivity of FDG PET/CT for diagnosing infective, inflammatory, and neoplastic processes can be exploited in this setting because these processes are often the common causes of FUO.

Place of 18F-FDG-PET with computed tomography in the diagnostic algorithm of patients with fever of unknown origin

There is evidence for the interest of (18)F-fluoro-deoxyglucose positron emission tomography with computed tomography ((18)F-FDG-PET/CT) in fever of unknown origin (FUO) clinical investigation. However, little and conflicting data exist about its place in the investigation procedure. The aim of this work was to evaluate the clinical value of (18)F-FDG-PET/CT in patients with FUO and identify patients who need early (18)F-FDG-PET/CT rather than a last-resort procedure. We performed a 2-year retrospective cohort study at the Nîmes University Hospital, France. A total of 79 patients (36 men, 43 women, mean age 54.0 ± 16.2 years) with FUO underwent (18)F-FDG-PET/CT. A final diagnosis was established in 61 (77.2 %) cases. Aetiologies of FUO were determined using (18)F-FDG-PET/CT findings in 45 (73.8 % of patients with diagnosis) cases. The sensibility and specificity value were 98 % and 87 %, respectively. The presence of adenopathy, low haemoglobin and increased C-reactive protein (CRP) were predictors of high-yield (18)F-FDG-PET/CT. (18)F-FDG-PET/CT may help to detect most causes of FUO. The predictors of high-yield (18)F-FDG-PET/CT found in this study can help identify patients likely to benefit from specific and early imaging techniques.

Superiority of 18F-FDG PET compared to 111In-labelled leucocyte scintigraphy in the evaluation of fever of unknown origin

To compare the accuracy of positron emission tomography (PET) using (18)F-FDG (Fluorodeoxyglucose) PET with (111)In-labelled leucocytes scintigraphy (LS) in patients with fever of unknown origin (FUO). Twenty-three consecutive patients with FUO were prospectively studied using whole-body LS and PET. Performance of the two modalities for identifying a cause of FUO was evaluated. Final diagnosis was based on biopsy, microbiological tests, clinical and imaging follow-up. Abnormal tracer uptake was seen in 3/23(13%) and 14/23(61%) patients on LS and PET respectively, suggesting a higher sensitivity (p < 0.01) for the latter. All LS positive cases were identified on PET and confirmed as infection. The causes of FUO in the other PET positive patients were: infection (n = 3), vasculitis (n = 3), non-infectious inflammatory conditions (n = 2) and cancer (n = 1). No specific diagnosis was reached in 2 patients. Of 13 patients without a definite diagnosis following PET and LS, 10 made a spontaneous recovery during the follow-up period and no definite cause for FUO was found on investigation. Still's disease, Polymyalgia rheumatica and Chronic fatigue syndrome/Myalgic encephalomyelitis were diagnosed in the remaining three patients during follow-up. The results thus showed an overall sensitivity of 86% for PET and 20% for LS (p < 0.01). The overall specificity for FDG PET was 78% as against 100% for LS. PET had a PPV of 86% and a NPV of 78% whereas LS had a PPV of 100% and a NPV of 40%. PET has a higher sensitivity than LS in identifying the aetiology of FUO. PET/PET-CT, where available, should be used as the non-invasive investigation of choice in the assessment of patients with FUO.

Fever of unknown origin (FUO) attributable to indolent lymphoproliferative disorder due to a plasmacytoma expressing immunoglobulin A

BackgroundThe most common categories causing fevers of unknown origin (FUOs) include infective rheumatic/inflammatory disorders and malignancies. Among neoplastic causes of FUOs, lymphomas, hepatomas, renal hypo-nephromas, and hepatomas are the most common. Other malignancies rarely present with FUOs (eg, multiple myeloma). Case ReportWe describe a 58-year-old man who presented with an FUO accompanied by night sweats, weight loss, and a groin mass. A biopsy of the groin mass (ie, his lymph node) was negative for infectious diseases, rheumatic or inflammatory diseases, and malignancies. Histochemical and immunological studies of the lymph node showed it to contain a plasmacytoma expressing immunoglobulin A (IgA). An immunohistochemical study of the plasma-cell infiltrate demonstrated strong CD138 staining. A bone marrow biopsy was negative for multiple myeloma. ConclusionWe believe this is the first reported rare case of an indolent, lymphoproliferative disorder attributable to an IgA-secreting plasmacytoma presenting as an FUO.

Fever of unknown origin (FUO) in an immunocompetent adult due to cytomegalovirus (CMV) with polyclonal gammopathy

Fever of unknown origin (FUO) may be due to infection, malignancy, collagen vascular/inflammatory disorders, or other causes. Cytomegalovirus (CMV) infection is a rare cause of FUO in immunocompetent adults. We present a case of FUO due to CMV in an immunocompetent adult with polyclonal gammopathy on serum protein electrophoresis (SPEP).

FDG PET/CT in Evaluation of Pyrexia of Unknown Origin

Pyrexia of unknown origin (PUO) is defined as fever above 38.5°C lasting for 3 weeks, of which at least 1 week has been spent in thorough investigation without a conclusive cause. Tuberculosis remains an important cause of PUO, particularly with the rising incidence of human immunodeficiency virus infection. It may strike virtually any organ in the body and can even mimic metastases especially in a known treated case of carcinoma. Bacterial infections, human immunodeficiency virus, hidden malignancy, sarcoidosis, and autoimmune disorders are some other important causes of PUO. Initial investigations include examination of blood, urine, stool, blood biochemistry, culture, etc. Typical radiologic investigations include chest radiography, computed tomography, and magnetic resonance imaging. Presented here is an atlas of cases where these investigations had been inconclusive but fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography demonstrated the site of pathology and directed histologic diagnosis.

Fever of unknown origin

This article reviews the classification and etiology of fever of unknown origin (FUO) in the adult population. A systematic diagnostic approach is discussed, equipping the NP to follow a careful history and physical, as well as focused diagnostic tests and procedures to determine the underlying cause of FUO.

The Diagnostic Role of FDG PET/CT in Patients with Fever of Unknown Origin

Objective: Fever of unknown origin (FUO) is a challenge for the physician and needs use of clinical, laboratory, and imaging studies and also invasive and/or non-invasive interventions to detect the etiology. The aim of present study was to assess the role of FDG PET/CT in determining the etiology in patients with FUO.Material and Methods: Twenty-four patients (median age 52, range 5-77 years, 6 female, 18 male) who were diagnosed with FUO were retrospectively analyzed in this study. Before the FDG PET/CT studies, none of them had a definitive reason for their diseases investigated by conventional radiological or scintigraphic methods, clinical and laboratory observations. Results: The positive result was achieved in 19 (79.2%) of 24 patients as findings of the FDG PET/CT. However, FDG PET/CT was useful for definitive diagnosis in 12 (63.2%) of 19 positive patients. Malignant diseases were determined to be the underlying cause of FUO in 5 (41.6%) of 12 patients. Noninfectious inflammatory causes were detected in 2 (16.7%) patients, infections were exhibited in 3 (25%) patients, and miscellaneous diseases demonstrated in 2 (16.7%) patients. In 7 patients the detected pathological uptakes on FDG PET/CT were not helpful for the definitive diagnosis. In remaining 5 patients who showed no pathological uptake in the FDG PET/CT, diagnosis could not be established by other methods, as well. The sensitivity, specificity, and positive and negative predictive values for the determination of FUO etiology were 92.3%, 45.4%, 63.1%, and 100% for FDG PET/CT.Conclusion: Our results demonstrate that FDG PET/CT seems to have considerable contribution to reveal the reason of undiagnosed patients with FUO investigated by conventional diagnostic methods, clinical and laboratory observations. Conflict of interest:None declared.

Diagnostic analysis of hospitalized patients with fever of unknown origin at department of infectious diseases

To explore the etiology, diagnostic methods and procedures for patients with fever of unknown origin (FUO) at department of infectious diseases. A total of 368 FUO patients admitted to department of infectious diseases from 2002 to 2009 were retrospectively reviewed. The correlations of etiologies and diagnostic methods with gender, age and progress of fever were analyzed. Among them, 112 (30.4%) cases were recognized in 2 weeks (diagnosis, n = 107; recovery with unknown causes, n = 5). A final diagnosis was established in 241 (94.1%) from the remaining 256 FUO patients (124 males, 132 females). Among them, the causes were infectious diseases (n = 193), rheumatologic/autoimmune diseases (n = 32) and hematological diseases/tumors (n = 16). The etiologies were infectious diseases (n = 95), rheumatologic/autoimmune diseases (n = 10), hematological diseases/tumors (n = 10) and unknown etiology (n = 9) in males respectively; infectious diseases (n = 98), rheumatologic diseases (n = 22), hematological diseases or tumors (n = 6) and unknown etiology (n = 6) in females respectively. Age of patients: < 14 yr (n = 10), 15 - 20 yr (n = 37), 21 - 50 yr (n = 110), 51 - 60 yr (n = 48) and > 61 yr (n = 51). Thermal process was < 4 weeks (n = 83) including 74 infectious diseases cases and > 8 weeks (n = 63), including infectious diseases (n = 21) and rheumatologic disease (n = 20). Some FUO outpatients may be promptly confirmed by history taking, physical examination and routine examinations. The major cause is infection. Other causes of FUO are infectious diseases, rheumatological/autoimmune diseases and hematological diseases/tumors. For the diagnosis of FUO patients, gender, age and thermal process should be considered.

Etiology and Clinical Features of Fever of Unknown Origin

To investigate the etiology and clinical features of fever of unknown origin (FUO). The clinical data including etiology, diagnostic approaches, and clinical features were retrospectively analyzed in 816 patients with FUO who were presented in our department from January 2000 to January 2009. Of these 816 FUO cases, 766 (93.9%) were confirmed to be with infective diseases(40.4%, n=330), connective tissue diseases (34.4%, n=281), malignant tumors (10.9%, n=89), other known diseases (8.1%, n=66), and unknown diseases (6.1%, n=50). The most common infective disease was tuberculosis (49.7%, 164/330), the most common connective tissue disease was adult-onset Stills disease (AOSD)(55.2%, 155/281), the most common malignant tumor was lymphoma(56.2%, 50/89), and the most common "other known disease" was Crohns disease(22.7%, 15/66). All lung cancer cases had obstructive pneumonia. Significantly more elderly patients suffered from infective diseases (49.4% vs.32.0%) and malignant tumor (15.6% vs. 6.4%) compared with the non-elderly (both P=0.0000), while the proportion of connective tissue diseases was significantly less than that of the non-elderly (17.9% vs. 50.1%, P=0.0000). Most FUO can be confirmed after careful examinations and analysis. The main cause of FUO is infective diseases, especially tuberculosis in the elderly. The connective tissue diseases and malignant tumors are also important causes.

Brucellosis as a Cause of Fever of Unknown Origin in Children Admitted to a Tertiary Hospital in the Aegean Region of Turkey

The aim of the study was to determine the role of brucellosis in children with fever of unknown origin (FUO) in the Aegean region of Turkey. For this purpose, the records of all children referred or admitted with diagnosis of FUO to the Department of Pediatric Infectious Diseases, Ege University Medical School, between 2003 and 2008 were scanned and 92 cases were identified retrospectively. Fifty-eight of these 92 children (63%) were diagnosed with infectious diseases, brucellosis being the most frequent cause (15.2%). Although several other infectious diseases do appear as a cause of FUO, brucellosis should be particularly considered as a differential diagnosis.

Prevalence of Connective Tissue Diseases in Egyptian Patients Presenting with Fever of Unknown Origin

Objective:To estimate the prevalence of connective tissue diseases in patients presenting with fever of unknown origin (FUO).Patients and methods:In this study thirty patients diagnosed as FUO (Group 1), in 2008, were included in an observational study and diagnostic workup. Additionally, retrospective analysis of seventy patients’ files (Group 2), for patients who presented with prolonged unexplained pyrexia to the same hospital in the previous two years, was performed. Patients were subjected to: full clinical assessment including full history taking, thorough clinical examination, laboratory investigations including the basic investigations for patients with prolonged fever, complete blood count, erythrocytes sedimentation rate, urine analysis and culture, blood culture, sputum culture and plain chest X ray. Further diagnostic work up and/or procedures were requested according to the potential diagnostic clues (PDC) present in every patient.Results:Out of 100 FUO patients, 50% were found to have infectious diseases, 24% were found to have connective tissue diseases, 8% miscellaneous causes and 7% neoplastic diseases (P < 0.05). In 11 patients no definite cause for FUO could be identified. Connective tissue patients were: eight systemic lupus patients (33.3%), five patients with familial mediterranean fever (20.8%), four patients with rheumatoid arthritis (16.6%), three patients (12.5%) with Still’s disease and Rheumatic fever and one patient with Behçet syndrome/Crohn’s disease (4.3%), (P < 0.05).Conclusions:Despite the advanced technology, FUO remains a challenging medical problem. Infections were the most common cause of FUO in Egypt, confirming the trends found in other parts of the world. There was an increased prevalence of connective tissue patients presented with prolonged unexplained fever. A keen clinical eye, meticulous history taking and repeated physical examination remained the most important diagnostic tools in FUO patients.

Etiological study of fever of unknown origin in patients admitted to medicine ward of a teaching hospital of Eastern India

Background:In a developing country, infectious disease remains the most important cause of fever, but the noncommunicable diseases, like malignancy, are fast becoming important differential diagnoses. An important clinical problem is the cases labeled as fever of unknown origin (FUO), which often evade diagnosis.Objective:The present study was undertaken to find the cause of FUO in a tertiary care hospital of eastern India.Materials and Methods:This is a prospective study of inpatients, with regard to both clinical signs and investigations.Results:The main diagnosis in the end was tuberculosis, closely followed by hematological malignancy. A substantial number of cases remained undiagnosed despite all investigations. The provisional diagnosis matched with the final in around two thirds of the cases. While for younger patients leukemia was a significant diagnosis, for older ones, extra-pulmonary tuberculosis was a main concern.Interpretation:In India, infectious disease still remains the most important cause of fever. Thus the initial investigations should always include tests for that purpose in a case of FUO.Conclusion:Geographic variations and local infection profiles should always be considered when investigating a case of FUO. However, some of the cases always elude diagnosis, although the patients may respond to empirical therapy.

Fever of unknown origin: A prospective study in Northern Iraq

Objectives: A wide variety of diseases are likely causes of fever of unknown origin (FUO). No fixed guidelines exist to direct the workup in these cases. We followed a diagnostic protocol to study the causes of FUO in Iraq, and to evaluate the contribution of clinical assessment and various investigations in making the final diagnosis. Methods: From March 2002 to September 2009, fifty five consecutive patients with FUO were admitted in a tertiary referral centre in Mosul, Iraq. The patients underwent a series of clinical and diagnostic evaluation in a prospective study, in an attempt to diagnose the underlying cause of fever. The benefit of history taking and clinical examination as directors of the diagnostic workup and the yield of various laboratory and imaging techniques were assessed.Results: Infections were the commonest causes of FUO (32.7%), followed by non-infectious inflammatory diseases (NIID) (25.4%), malignancies (16.4%) and miscellaneous causes (5.4%). No diagnosis was made in 20% of cases. Of infections, tuberculosis was the most important single cause of fever, while various vasculitides and non-Hodgkin's lymphoma were the commonest NIID and malignant disease, respectively. Symptoms of the patients were of little benefit in directing subsequent investigations, but the physical signs were more useful; finding enlarged lymph nodes was significantly associated with malignant diseases (p=0.009). Anaemia, high ESR and elevated liver enzymes were common and bear no significant association with any disease category. Chest radiograph and abdominal ultrasound were helpful initial imaging studies. CT scan of the chest was shown a useful diagnostic procedure.Conclusion: Together with infections, NIID are important causes of FUO in Iraq. Careful physical examination and a systematic approach on investigations are usually rewarding in reaching the diagnosis.

A meta-analysis of the value of fluorodeoxyglucose-PET/PET-CT in the evaluation of fever of unknown origin

The diagnosis of patients with fever of unknown origin (FUO) remains a challenging medical problem for internal medicine. A reliable estimate of the diagnostic performance of FDG-PET and FDG-PET/CT in the assessment of FUO unidentified by conventional workup has never been systematically assessed, and present systematic review was aimed at this issue. A systematic search for relevant studies was performed of the PubMed, Embase, and Cochrane databases. Methodological quality of each study was assessed. Sensitivity, specificity and area under the curve (AUC) were meta-analyzed. Subgroup analyses were performed if results of individual studies were heterogeneous. The inclusion criteria were met by nine studies. Overall, the studies had good methodological quality. Pooled sensitivity and specificity of FDG-PET for the detection of FUO were 0.826 (95% CI; 0.729-0.899) and 0.578 (95% CI; 0.488-0.665), respectively, and the AUC was 0.810. Heterogeneity among the results of FDG PET studies was present (QSE=12.40, I2=67.7%; QSp=35.98, I2=88.9%). Pooled sensitivity and specificity of FDG-PET/CT were 0.982 (95% CI; 0.936-0.998) and 0.859 (95% CI; 0.750-0.934), respectively, and the AUC was 0.947. We did not find any statistical differences in the AUC and Q* index between FDG-PET and FDG-PET/CT (Z=0.566, p>0.05). Although the FDG-PET studies that we examined were heterogeneous, FDG-PET appears to be a sensitive and promising diagnostic tool for the detection of the causes of FUO. FDG-PET/CT should be considered among the first diagnostic tools for patients with FUO in whom conventional diagnostics have been unsuccessful.

Diagnostic value of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in patients with fever of unknown origin

Background While fever of unknown origin (FUO) remains a challenging problem in clinical practice, fluorine-18 fluorodeoxyglucose ( 18F-FDG) positron emission tomography/computed tomography (PET/CT) has been considered helpful in diagnosing its cause. The present study is set to evaluate the diagnostic value of PET/CT for patients with FUO. Methods We analyzed the records of 48 patients with FUO (34 men and 14 women; mean age of 57-year-old with a range between 24- and 82-year-old). The patients were examined by 18F-FDG PET/CT and the results were compared to a final diagnosis that was established by additional procedures. Results A final diagnosis was established for 36 patients (75%). Among them, 15 patients had infectious diseases, 12 patients had malignancies, and 9 patients had non-infectious inflammatory diseases. Thirty-two abnormal PET/CT results correctly revealed the source of fever (true-positives). Abnormal PET/CT results were considered false-positives for 8 patients without diagnoses. Normal PET/CT results in 4 patients with no diagnoses were classified as true-negatives. Four patients with normal PET/CT results with diagnosed cause for FUO were considered false-negatives. Therefore, PET/CT had a positive predictive value of 80%, a negative predictive value of 50%, a sensitivity of 89%, and a specificity of 33% in patients with FUO. Conclusions Our study demonstrated that FDG-PET/CT is a valuable imaging tool for the identification of the etiology in patients with FUO. The results suggest that this procedure may be considered as a second-line test, especially when conventional structural imaging was normal or unable to distinguish lesions from benign and malignant.

A Case with Fever of Unknown Origin Diagnosed as Wegener Granulomatosis

Fever of unknown origin (FUO) was described in 1961 by Petersdorf and Beeson as a fever above 38.3°C that lasts more than three weeks and cannot be diagnosed despite a one-week hospitalized examination. In 1991, Durack and Street made a different FUO description for patients with nosocomial infections, human immunodeficiency virus (HIV) and neutropenia. Along with this reconsideration, the investigation period was limited to one week of investigation, three days of hospitalization or three clinical visits. In the literature, the most frequent cause of FUO is infections followed by neoplasms and connective vascular diseases, respectively. The etiology in 5-15% of patients can not be diagnosed despite detailed examination. Here, we present a 75-year-old patient admitted to the hospital with a two-week history of fever, fatigue and lack of appetite. He had been examined in the infection and lung diseases clinics over a three–month period without diagnosis. In our internal medicine clinic, we diagnosed the patient as Wegener granulomatosis and a satisfactory response to the therapy was observed. (Turk J Rheumatol 2010; 25: 159-61)

Diagnostic yield of bone marrow examination in HIV associated FUO in ART naïve patients

A bone marrow (BM) aspiration and biopsy is often believed to be a much needed diagnostic procedure in the work up of patients with fever of unknown origin (FUO), especially in the setting of AIDS. Is it worthwhile to proceed with this invasive diagnostic method? The usefulness of a BM aspiration or biopsy to assist in the diagnosis of FUO or prolonged fever in AIDS patients has been reported previously to range from 4% to 40%. The purpose of this study was to assess the usefulness of a BM aspiration and biopsy in diagnosing the cause of FUO in patients with AIDS and to identify the utility of the procedure for the diagnosis of malignancies/other hematological disorders resulting in the FUO. In this study, comprising of 30 patients, we have tried to find the diagnostic yield of bone marrow examination in finding the etiology of "FUO associated with HIV infection". Though similar studies have been reported in the literature but it is lacking from eastern India. The majority of BM examination in this series revealed infections followed by hematological disorders. Our study showed the diagnostic yield of bone marrow examination in "HIV associated FUO" to be 26.7%. It was found to be positive in 33.3% of the patients, who had the final diagnosis of an infective etiology and 100% of the patients, who had a final diagnosis of an underlying hematological etiology.