Fever of Unknown Origin

9/04/02 (Vicas)

Question: What etiologies are associated with fever of unknown origin, and how is this condition properly investigated?

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Unique Identifier:9413426

Authors: de Kleijn EM. van Lier HJ. van der Meer JW.

Institution: Department of Medicine, University Hospital St. Radboud, Nijmegen, The Netherlands.

Title: Fever of unknown origin (FUO). II. Diagnostic procedures in a prospective multicenter study of 167 patients. The Netherlands FUO Study Group.

Source: Medicine. 76(6):401-14, 1997 Nov.

Abstract: From January 1992 until January 1994, we used a standardized diagnostic protocol for the 167 immunocompetent patients with fever of unknown origin (FUO) admitted on the internal medicine wards in all 8 university hospitals in the Netherlands. This protocol consisted of a standardized coded history and standardized physical examination for all 167 patients. A number of additional obligatory investigations had to be performed in the first week of admission for all patients, and all potentially diagnostic clues (PDCs) thus retrieved had to be registered. In the presence of PDCs, specific investigations had to be performed based on the differential diagnosis. In the absence of PDCs or in the presence of only misleading PDCs, patients underwent a screening 2-staged diagnostic protocol. In 162 (97%) patients, PDCs were present after 1 week of admission. In 61 patients these PDCs were all misleading. The likelihood of reaching a diagnosis in patients with PDCs was not significantly higher than that in patients without PDCs, probably because of the high proportion of misleading PDCs. The likelihood of establishing a diagnosis was significantly lower (< 10%) only for patients with recurrent fever, normal erythrocyte sedimentation rate (ESR), and normal hemoglobin. All other PDCs were not significantly different in patients with a diagnosis compared with patients without a diagnosis. The screening 2-staged diagnostic protocol proved useful in 10 of 43 patients in whom it was used. The screening value of immunologic and microbiologic serology and endocrine investigations was nil; these investigations probably should be performed only when PDCs for the disease searched for are present. Scintigraphic techniques, echocardiography, and other imaging procedures were never helpful in our population in the absence of PDCs. Many patients with FUO had nonspecific anemia and disturbed liver chemistry. In the presence of these findings alone, without other more specific PDCs, the likelihood of reaching a diagnosis with help of bone marrow aspiration was nil, and with help of liver biopsy, it was low. Enteric biopsy was never helpful. If lymphadenopathy was confined to the cervical or inguinal region (with negative chest X-ray and abdominal ultrasound), lymph node biopsy was not helpful, in contrast to patients having generalized lymphadenopathy, in whom the technique had a yield of 79%. As shown in this study, the search for PDCs remains an important tool for establishing the diagnosis in patients with FUO, although in many cases these PDCs appear to be misleading. Directed diagnostic workup--using the PDCs retrieved by repeated, meticulous history taking and physical examination--remains the most efficient and intellectually satisfactory way to solve the problem of FUO in the individual patient. A standard protocol in patients with FUO in whom the obligatory investigations, as used by us, do not lead to the diagnosis can be limited to the tests that proved to be of some use as screening procedure: temporal biopsy in patients older than 55 years; fundoscopy; serology (Western blot) for Yersinia enterocolitica; serum for cryoglobulin at an early stage of the diagnostic process; and bone biopsy, liver biopsy, abdominal computed tomography (CT), and chest CT at a later stage. Repeating a thorough history-taking, physical examination, and obligatory investigations and waiting for PDCs to appear probably is better than ordering more screening investigations in the hope that something abnormal will come up. Supportive treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) can be helpful at this stage. Only rarely do patients deteriorate while using NSAIDs without presenting new PDCs. In these rare patients, further diagnostic workup should be performed or a therapeutic trial with, for example, antibiotics, steroids, or antituberculous agents started.

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Unique Identifier:9413425

Authors: de Kleijn EM. Vandenbroucke JP. van der Meer JW.

Institution: Department of Medicine, University Hospital St. Radboud, Nijmegen, The Netherlands.

Title: Fever of unknown origin (FUO). I A. prospective multicenter study of 167 patients with FUO, using fixed epidemiologic entry criteria. The Netherlands FUO Study Group.

Source: Medicine. 76(6):392-400, 1997 Nov.

Abstract: Internal medicine wards in all 8 university hospitals in the Netherlands participated in this prospective study of fever of unknown origin (FUO) from January 1992 until January 1994 in order to update information on the spectrum of diseases causing FUO. We used fixed epidemiologic entry criteria to achieve completeness of enrollment and to avoid unintended selection bias. After entry, immunocompetent patients were included using criteria for FUO according to Petersdorf and Beeson (30). A standardized diagnostic protocol was used, and potentially diagnostic clues (PDCs) and their use in the diagnostic process were prospectively registered. Thus, the criteria of classic FUO have been adjusted to modern times: immunocompromised patients are excluded, and the time-criterion "1 week in hospital without a diagnosis" has been replaced by a quality-criterion stating that certain investigations must be performed as a minimum, and PDCs must be followed adequately for at least 1 week, without a diagnosis being reached. A total of 167 immunocompetent patients with FUO were thus retrieved, of whom 43 (25.7%) had infections, 21 (12.6%) had neoplasms, and 40 (24.0%) had noninfectious inflammatory diseases. No diagnosis was made in 50 patients (29.9%), 37 of whom recovered spontaneously. This study confirms the changing spectrum of diseases causing FUO. Indeed, as shown by another recent study, the group of patients with FUO in whom no diagnosis can be made is expanding, and mostly it concerns self-limiting or benign fevers. Others have suggested that this trend is not really occurring (29). We did not place patients with diseases of unknown origin in the "nondiagnosis" group, and indeed made presumptive diagnoses when necessary. Nevertheless, this category of undiagnosed fevers is increasing. We believe that the higher percentage of undiagnosed cases can be attributed to the greater use of advanced diagnostic techniques attendant on an increased number of self-limited illnesses in patients meeting criteria for FUO. Because of ongoing development in diagnostic techniques and the prospective influence on the spectrum of diseases causing FUO, studies should be performed regularly to update information on this subject. Because the number of outpatient evaluations for FUO is expected to increase, patients seen on an outpatient basis should be included in future studies. To avoid unwanted selection bias, fixed epidemiologic entry criteria should be used to ensure completeness of enrollment. To shorten the period of collecting data, multicentric studies can be done using standardized diagnostic protocols. In patients with recurrent fever or fever lasting longer than 6 months, the chance of reaching a diagnosis is significantly lower, and especially in this group one should exercise the greatest caution to avoid abundant and extensive diagnostic procedures. The diagnostic process in patients with FUO remains an intriguing problem in medicine. Recent microbiologic techniques may be useful as an approach to the relatively large proportion of patients in whom we now fail to make a diagnosis.

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Unique Identifier:9284789

Authors: Arnow PM. Flaherty JP.

Institution: Department of Medicine, University of Chicago, University of Chicago Hospitals, IL 60637, USA.

Title: Fever of unknown origin. [see comments.]. [Review] [33 refs]

Source: Lancet. 350(9077):575-80, 1997 Aug 23.

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Unique Identifier:8629872

Authors: Knockaert DC. Dujardin KS. Bobbaers HJ.

Institution: Department of General Internal Medicine, Gasthuisberg University Hospital, Leuven, Belgium.

Title: Long-term follow-up of patients with undiagnosed fever of unknown origin.

Source: Archives of Internal Medicine. 156(6):618-20, 1996 Mar 25.

Abstract: BACKGROUND: A casual diagnosis cannot be established in 10% to 25% of the patients who are studied for fever of unknown origin (FUO). The long-term clinical outcome of these patients cannot be inferred from the literature. This study describes the results of a 5-year follow-up of 61 patients studied for FUO and discharged from the hospital with no causal diagnosis being established. METHODS: Patients meeting the classic criteria for FUO who were studied in the 1980s and discharged from the hospital without a casual diagnosis were followed up for at least 5 years or until death. Follow-up was performed by review of the patients' medical records or by consulting the treating physician and occasionally the patients themselves. The final diagnosis, clinical course (resolution of the fever and required treatments), and morality rate were studied. RESULTS: Of a cohort of 199 patients with FUO, 61 individuals (30%) were discharged from the hospital without a final diagnosis being established. A definite diagnosis could be established in 12 cases, mostly (eight of 12) within 2 months after discharge. Thirty-one individuals became symptom free during hospitalization or shortly following discharge. Eighteen patients had persisting or recurring fever for several months or even years after discharge, but 10 of them were considered to be finally cured. Four patients were treated with corticosteroids and six patients required intermittent therapy with nonsteroidal anti-inflammatory agents. Six patients died, but the cause of death was considered to be related to the disease that caused FUO in only two cases. CONCLUSION: No single disease, particularly not tuberculosis, was found to be a cause of undiagnosed FUO. Most cases resolved spontaneously, and corticosteroids were seldom required. Most symptomatic patients could be treated with nonsteroidal anti-inflammatory drugs. The mortality rate in patients with undiagnosed FUO who were followed up for 5 years or more was only 3.2%.