Fever of unknown origin in HIV/AIDS patients

Fever of unknown or uncertain origin (FUO) constitutes a common clinical challenge in patients infected with HIV. It is usually caused by disseminated opportunistic infection, and the relative frequency of each cause of FUO is influenced by multiple factors including CD4 count, geographic setting, and local prevalences of infectious agents, which may provide clues to the diagnosis. Infections presenting as FUO in the HIV population occur most often in the late stages of the disease and high diagnostic suspicion for mycobacterial disease should be maintained when evaluating these patients, particularly in areas of high prevalence. This article discusses the causes, diagnosis, and treatment of FUO in HIV-infected individuals.     

Fever of unknown origin: historical and physical clues to making the diagnosis

Fever of unknown origin (FUO) has fascinated and perplexed clinicians for over a century. No published guidelines exist on the approach to FUO, and studies have demonstrated that a diagnosis is never established in up to 30% of cases. A comprehensive history and physical examination are the keys to establishing a diagnosis in patient with FUO. This article provides a systematic approach to the diagnosis of FUO by delineating the most important elements of a comprehensive history and physical examination.     

The value of CMV and fungal PCR for monitoring for acute leukaemia and autologous stem cell transplant patients

Both CMV and fungal infections have been suggested to be causes of fever of unknown origin (FUO) in neutropenic patients. The aim of this prospective, blinded study was to use nucleic acid techniques for monitoring of 20 acute leukemia and 15 autologous stem cell transplant (SCT) patients. Blood samples were taken weekly and examined for fungal and CMV DNA by PCR and CMV mRNA by NASBA. 387 samples were analysed. Fungal DNA was detected in 9 samples. Four samples were positive for Aspergillus and 6 for Candida DNA (1 sample positive for both). Candida PCR was positive in 2 patients with FUO, 1 patient with a bacterial infection, 1 patient with fungaemia, and in 1 afebrile patient. Three patients had verified Candida infections. One was PCR positive and 2 were negative. Three patients with positive Aspergillus PCR had pneumonias and 1 patient had a FUO. CMV DNA was found in 19 samples from 15 CMV seropositive patients. CMV mRNA was detected in 1 sample. Two patients had infections possibly caused by CMV. No antiviral therapy was give and both recovered. PCR for Aspergillus might be helpful for the diagnosis of pneumonia while neither CMV nor Candida PCR conferred diagnostic benefits in this study.     

Diagnostic utility of bone marrow examination for the assessment of patients with fever of unknown origin: a 10‐year single‐centre experience

Bone marrow (BM) examination is included in the diagnostic algorithm of fever of unknown origin (FUO), although its role is not clearly determined. The purpose of this study was to assess the role of BM studies in patients with FUO. We retrospectively reviewed 45 consecutive patients (25% human immunodeficiency virus‐positive) with FUO who underwent a BM study in the University Hospital of Salamanca from 2000 to 2010. We analysed the diagnostic role of BM smears, multiparameter flow cytometry analysis, histology and microbiological cultures. Five patients (11%) were finally diagnosed by BM study (three had an infectious disease and two were found to have haematological malignancies), all of whom were immunocompetent patients. Histology was the most useful study (diagnosis was obtained in 4/5 patients), while BM cultures did not establish the final diagnosis in any patient. Flow cytometry established the diagnosis in one patient, although this patient was also diagnosed by histology. In conclusion, BM study is useful for establishing the aetiology of FUO. BM biopsy for histological examination should be always mandatory if a BM examination is performed.     

Fever of unknown origin in older adults

Evaluation of elderly patients who have fever of unknown origin (FUO) requires a different perspective from that needed for young patients. Differential diagnosis often varies with age, and presentation of the disease frequently is nonspecific and symptoms difficult to interpret. Noninfectious diseases are the most frequent cause of FUO in the elderly and temporal arteritis the most frequent specific cause. Tuberculosis is the most common infectious disease associated with FUO in elderly patients. FUO often is associated with treatable conditions in the elderly. Therefore, intensive, accelerated evaluation is necessary, as the lack of physiologic reserve makes this population vulnerable to irreversible changes and functional deterioration.     

Fieber ungeklärter Ursache

Fever of unknown origin (FUO) is defined as sustained unexplained fever despite intensive diagnostic evaluation and represents a particular diagnostic challenge. It can be classified into different categories, e.g. classical, nosocomial, neutropenic and HIV-associated FUO, which is based on the patient-specific clinical and immunological situation. Infections, malignant diseases and non-infectious inflammatory diseases have to be considered as the most important causes of FUO; however, no definitive diagnosis can be established in a substantial number of FUO patients despite an extensive diagnostic work-up. The present review focuses on the important diagnostic aspects as well as therapeutic options in FUO patients.     

Tuberculosis or systemic lupus erythematosus? A diagnostic and therapeutic dilemma

The diagnosis of patients with fever of unknown origin (FUO) is often problematic because the range of possible differential diagnoses is broad. We report on a case in which a patient presented with FUO and was subsequently found to have both a collagen vascular disease and an intercurrent infection. Treatment for the collagen vascular disease with corticosteroids exacerbated the intercurrent infection. The problems in the diagnosis and management of such cases are discussed.     

Fever of unknown origin (FUO) caused by multiple myeloma: the diagnostic value of the Naprosyn test

Fever of unknown origin (FUO) remains a difficult diagnostic problem. The causes of FUO have changed over the years. Neoplastic disorders have now displaced infectious diseases as the most common cause of FUOs. Most neoplasms are associated with no or low-grade temperatures, with some important exceptions. Hypernephromas and lymphomas are neoplasms typically associated with high spiking fevers or may present as FUOs. Hematologic malignancies, that is, the acute and chronic leukemias, myeloproliferative disorders, and multiple myeloma, do not usually present with acute fevers or as FUOs. We present an elderly male patient who presented with an FUO, whose history is significant for multiple myeloma in remission. Differential diagnostic possibilities in this patient included plasma cell leukemia, relapse of multiple myeloma, secondary/superimposed malignancy, or opportunistic infection. The main differential diagnosis for his FUO was between neoplastic and infectious disorders. As part of the diagnostic workup, a Naprosyn test (naproxen 375 mg [by mouth] every 12 hours for 3 days) was used to differentiate neoplastic from infectious causes of FUO in this patient. The Naprosyn test was positive, which indicated a neoplastic explanation for the patient's FUO and eliminated, along with the infectious disease workup, an infectious explanation for his FUO. The patient's FUO was finally determined to be the result of a relapse of multiple myeloma and not of a secondary malignancy or malignant transformation of myeloma into plasma cell leukemia. We conclude the Naprosyn test remains a valuable diagnostic test to use to narrow differential diagnostic possibilities in patients with FUOs when a malignancy is a diagnostic consideration.     

Fever of unknown origin caused by late-onset rheumatoid arthritis

Fever of unknown origin (FUO) is always a diagnostic challenge. The causes of FUO are legion and may be due to malignancy, infection, collagen vascular disease, and a variety of other unusual disorders. Currently, malignancies-followed by infectious etiologies-are the most common cause of FUO. We present an elderly female patient with an FUO who was thought to have subacute bacterial endocarditis because of an antecedent history of recent dental work. Subacute bacterial endocarditis was ruled out on the basis of negative cultures and negative transesophageal echocardiography. No evidence for an infectious disease or neoplastic etiology could be demonstrated in this patient. The diagnosis of FUO is most difficult when there is a paucity of clues from the history and physical examination, as was the case in this patient. Nonspecific laboratory tests included highly increased erythrocyte sedimentation rate (>or=100 mm/h), highly increased C-reactive protein, relative lymphocytopenia, and chronic thrombocytosis. These findings are compatible with a variety of infectious and inflammatory disorders. No evidence could be found for vasculitis. The only laboratory diagnostic findings present in her case were a highly increased rheumatoid factor titer and perinuclear antineutrophilic cytoplasmic antibody level. Polymyalgia rheumatica/temporal arteritis, systemic lupus erythematosus, and adult Still's disease were ruled out. The patient's FUO was best explained by the finding of late-onset rheumatoid arthritis (LORA), which is characterized by acute onset in elderly patients without the usual musculoskeletal manifestations of rheumatoid arthritis. Both the highly increased rheumatoid factor titer and perinuclear antineutrophilic cytoplasmic antibody level in the absence of an alternate explanation indicate that the FUO in this patient was caused by LORA.     

A comprehensive evidence-based approach to fever of unknown origin

BACKGROUND: Fever of unknown origin (FUO) is defined as a temperature higher than 38.3 degrees C on several occasions and lasting longer than 3 weeks, with a diagnosis that remains uncertain after 1 week of investigation. METHODS: A systematic review was performed to develop evidence-based recommendations for the diagnostic workup of FUO. MEDLINE database was searched (January 1966 to December 2000) to identify articles related to FUO. Articles were included if the patient population met the criteria for FUO and they addressed the natural history, prognosis, or spectrum of disease or evaluated a diagnostic test in FUO. The quality of retrieved articles was rated as "good," "fair," or "poor," and sensitivity, specificity, and diagnostic yield of tests were calculated. Recommendations were made in accordance with the strength of evidence. RESULTS: The prevalence of FUO in hospitalized patients is reported to be 2.9%. Eleven studies indicate that the spectrum of disease includes "no diagnosis" (19%), infections (28%), inflammatory diseases (21%), and malignancies (17%). Deep vein thrombosis (3%) and temporal arteritis in the elderly (16%-17%) were important considerations. Four good natural history studies indicate that most patients with undiagnosed FUO recover spontaneously (51%-100%). One fair-quality study suggested a high specificity (99%) for the diagnosis of endocarditis in FUO by applying the Duke criteria. One fair-quality study showed that computed tomographic scanning of the abdomen had a diagnostic yield of 19%. Ten studies of nuclear imaging revealed that technetium was the most promising isotope, showing a high specificity (94%), albeit low sensitivity (40%-75%) (2 fair-quality studies). Two fair-quality studies showed liver biopsy to have a high diagnostic yield (14%-17%), but with risk of harm (0.009%-0.12% death). Empiric bone marrow cultures showed a low diagnostic yield of 0% to 2% (2 fair-quality articles). CONCLUSIONS: Diagnosis of FUO may be assisted by the Duke criteria for endocarditis, computed tomographic scan of the abdomen, nuclear scanning with a technetium-based isotope, and liver biopsy (fair to good evidence). Routine bone marrow cultures are not recommended.     

Fever of unknown origin in the elderly

Fever of unknown origin (FUO) means fever that does not resolve itself in the period expected for self-limited infection and whose cause cannot be ascertained despite considerable diagnostic efforts. The differential diagnosis is often different in older patients, and presentation of disease is frequently nonspecific and symptoms are difficult to interpret. Multisystem disease has emerged as the most frequent cause of FUO in the elderly, and temporal arteritis is the most frequent specific diagnosis. Infections, particular tuberculosis, remain an important group. FUO is often associated with treatable conditions in this age group. Early recognition and prompt initiation of appropriate empirical therapy are cornerstones of the strategy.     

Fever of unknown origin caused by multiple myeloma: a report of 9 cases

BACKGROUND: Most authorities regard multiple myeloma as a rare cause of fever and not a cause of fever of unknown origin (FUO). OBJECTIVE: To describe a series of patients with FUO caused by multiple myeloma. METHODS: We reviewed the clinical features of 9 patients seen at Mayo Clinic from January 1, 1975, to February 1, 2001, with FUO caused by multiple myeloma. RESULTS: Fever of unknown origin caused by multiple myeloma was found in 9 patients (6 men and 3 women). All patients satisfied accepted criteria for FUO. The mean +/- SD time from the onset of fevers to the initial physician evaluation was 4.8 +/- 2.0 weeks. The mean time from the initial physician evaluation to the diagnosis of multiple myeloma was 11.4 +/- 6.5 weeks. The mean age at diagnosis of multiple myeloma was 55.9 +/- 6.9 years. All 9 patients were anemic. Peripheral blood smears were available for 8 patients, and all had rouleaux formations. All 9 patients underwent exhaustive testing to determine the cause of fevers. Further testing was done in 6 patients subsequent to the diagnosis of multiple myeloma. Acetaminophen or nonsteroidal anti-inflammatory drugs or both relieved fevers in all patients who received them. All 8 patients who received chemotherapy experienced resolution of fevers. The median actuarial survival of the patient cohort was 38 months. CONCLUSIONS: Multiple myeloma can cause FUO. When appropriate, clinicians should include multiple myeloma in the differential diagnosis of FUO to reduce unnecessary testing, rapidly establish the diagnosis, and initiate effective treatments.     

Standardised work-up programme for fever of unknown origin and contribution of magnetic resonance imaging for the diagnosis of hidden systemic vasculitis

BACKGROUND: Fever of unknown origin (FUO) is a diagnostic challenge. Rheumatologists are often in charge of patients with FUO because the vasculitides, especially, are potential and common causes of FUO. OBJECTIVE: To evaluate the value of a standardised investigation to identify the cause of FUO. METHODS: A standardised work-up programme for patients with FUO was started at the beginning of September 1999. The rate of identified causes of FUO was compared between all patients with FUO admitted to a tertiary care centre of rheumatology between January 1996 and August 1999 (control group) and September 1999 and January 2003 (work-up group). In January 2002 magnetic resonance imaging (MRI) was added to the investigation. RESULTS: 67 patients with FUO were identified--32 before and 35 after institution of the work-up programme. Before implementation 25% of all patients with FUO remained undiagnosed, after implementation 37%. After institution of the investigation the percentage of patients with vasculitides increased significantly from 6% (n = 2) to 26% (n = 9, p = 0.047, Fisher's exact test). This increase could be attributed to the addition of MRI in 2002. When all patients with FUO before 2002 (n = 55) and thereafter (n = 12) were compared the prevalence of systemic vasculitis increased from 11% (n = 6) to 42% (n = 5, p = 0.021). CONCLUSION: Implementation of a standardised work-up programme for FUO did not improve the overall rate of diagnosis. Addition of MRI significantly increased the diagnosis of systemic vasculitis as the underlying cause of FUO. MRI should be included in the investigation of patients with FUO when vasculitis is suspected.     

Pulmonary complications following hematopoietic stem cell transplantation: diagnostic approaches

Pulmonary complications are a significant cause of morbidity and mortality in hematopoietic stem cell transplant recipients. Pulmonary infiltrates in such patients pose a major challenge for clinicians because of the wide differential diagnosis of infectious and noninfectious conditions. It is rare for the diagnosis to be made by chest radiograph, and commonly these patients will need further invasive and noninvasive studies to confirm the etiology of the pulmonary infiltrates. This review describes the role of the different diagnostic tools available to reach a diagnosis in a timely manner in this patient population.     

Fever of unknown origin in a Mediterranean survey from a division of internal medicine: report of 91 cases during a 12-year-period (1991–2002)

Despite the availability of all advanced diagnostic tools, fever of unknown origin (FUO) remains a diagnostic challenge for physicians. The objective was to define, through a retrospective study, the categories of the diseases of Sicilian patients admitted at the Department of Clinical Medicine and Emerging Diseases, University of Palermo, Italy, for classical FUO. Using the registration system for patients admitted from 1991 to 2002, 508 charts of patients admitted because of fever were reviewed. Of these, only 91 patients fulfilled the criteria for classical FUO. The origin of FUO was diagnosed in 62 (68.1%) patients. Infection was the most common cause of FUO with 29 cases (31.8% of total of FUO), neoplasms accounted for 13 cases (14.2%), collagen vascular disease for 11 cases (12.0%), and miscellaneous for 9 cases (9.8%). Undiagnosed FUO were 29 (31.8%) and, of them, 22 cases were followed-up for 2 years. A definite diagnosis could be established only in 8 cases, 13 subjects completely recovered and 4 of them died. In the 73.4% of cases, the FUO have been the result of misleading factors in the diagnostic approaches as made by the physician. The results of our study are similar to those already reported by other authors in other populations, with infections as first, neoplasm as second, and collagen vascular diseases as third most important causes of FUO. In our study the prognosis for undiagnosed FUO cases was good, but a definite diagnosis could be established only in few cases. Therefore, further multicentric, prospective studies of good design are required.     

Primary antiphospholipid syndrome: a cause of fever of unknown origin

Antiphospholipid syndrome (APS) is defined as the occurrence of thrombosis, recurrent miscarriage, or both in association with laboratory evidence of persistent antiphospholipid antibodies. Owing to protean manifestations and laboratory studies, the diagnosis may be difficult. Because the other signs and symptoms of thrombosis are predominant, prolonged fever is not usually the main clinical finding. We describe a patient who presented with fever of unknown origin (FUO) and was found to have thromboses of the splenic vein, the superior mesenteric vein, and the portal vein due to the primary antiphospholipid syndrome. We also reviewed the medical literature (Medline 1966-2001), including the main FUO series of the previous 40 years, and laparotomy series for FUO. We conclude that although very rare, primary APS and thrombosis may present with FUO. APS should be considered in the differential diagnosis of prolonged fever associated with thrombosis.     

Fever of unknown origin: subacute thyroiditis versus typhoid fever

Fever of unknown origin (FUO) is not infrequently a diagnostic dilemma for clinicians. Common infectious causes include endocarditis and abscesses in adults, and noninfectious causes include neoplasms and certain collagen vascular diseases, for example, polymyalgia rheumatica, various vasculitides, and juvenile rheumatoid arthritis (adult Still's disease). Subacute thyroiditis is a rare cause of FUO. Among the infectious causes of FUO, typhoid fever is relatively uncommon. We present a case of FUO in a traveler returning from India whose initial complaints were that of left-sided neck pain and angle of the jaw pain, which initially suggested the diagnosis of subacute thyroiditis. After an extensive FUO workup, when typhoid fever is a likely diagnostic possibility, an empiric trial of anti- Salmonella therapy has diagnostic and therapeutic significance. The presence of relative bradycardia, and response to quinolone therapy, was the basis of the clinical diagnosis of typhoid fever as the explanation for this patients FUO. This case illustrates the diagnostic difficulties in assessing patients with FUO with few diagnostic findings.     

Fever of Unknown Origin in Turkey

Abstract. Background: The etiology of fever of unknown origin (FUO) includes primarily infectious, collagen-vascular and neoplastic diseases. The distribution of the disorders causing FUO may differ according to the geographic area and the socioeconomical status of the country. Moreover, the developments in radiographic and microbiologic methods have changed the spectrum of diseases causing FUO. Materials and Methods: We reviewed 117 cases that fulfilled the criteria of FUO followed in our department during the period 1984 to 2001. Results: The etiology of FUO was infectious diseases in 34% of the patients, collagen-vascular diseases in 23%, neoplasms in 19% and miscellaneous diseases in 10%. In 14% of the cases the etiology could not be found. The three leading diseases were tuberculosis (24%), lymphomas (19%) and adult-onset Stills disease (11%). Tuberculosis was found to be a more common cause of FUO than reported in studies in developed countries. Invasive procedures helped to establish the diagnosis in 50 out of 92 patients (43%). As a final diagnostic procedure, laparotomy aided the establishment of a diagnosis in 15 out of 20 patients (75%). Conclusion: Although the relative rate of infectious disease as etiologic category is less commonly encountered, infectious disease, especially tuberculosis, remains a common cause of FUO. Although several diseases may lead to FUO, lymphomas, adult-onset Stills disease and particularly tuberculosis should be considered in the differential diagnosis of a patient admitted with FUO.     

Lung transplant infection

Lung transplantation has become an accepted therapeutic procedure for the treatment of end‐stage pulmonary parenchymal and vascular disease. Despite improved survival rates over the decades, lung transplant recipients have lower survival rates than other solid organ transplant recipients. The morbidity and mortality following lung transplantation is largely due to infection‐ and rejection‐related complications. This article will review the common infections that develop in the lung transplant recipient, including the general risk factors for infection in this population, and the most frequent bacterial, viral, fungal and other less frequent opportunistic infections. The epidemiology, diagnosis, prophylaxis, treatment and outcomes for the different microbial pathogens will be reviewed. The effects of infection on lung transplant rejection will also be discussed.     

Intravascular large B-cell lymphoma or intravascular lymphomatosis: report of a case diagnosed by testicle biopsy

Intravascular large B-cell lymphoma or intravascular lymphomatosis (IVL) is an extremely rare form of non-Hodgkin's lymphoma. The most common clinical sign is fever of unknown origin (FUO). Histologically, there is proliferation of malignant lymphoid cells within vascular lumina. Cytologically, the cells have features similar to those found in classical large cell lymphoma. Examination of pulmonary artery blood showed the presence of this abnormal population in our patient; to the best of our knowledge there are only four other. reports of detection of circulating tumor cells in IVL. The outcome is very poor. The diagnosis is most frequently made after biopsy of skin or brain but is often established post mortem. We present what is--to our knowledge--the first reported case of IVL diagnosed after biopsy of a testicle. In the event of FUO and suspicion of a malignancy, IVL--although very rare--should be one of the differential diagnoses.