Fever of Unknown Origin (FUO)

Updated: Mar 20, 2017
  • Author: Sandra G Gompf, MD, FACP, FIDSA; Chief Editor: Michael Stuart Bronze, MD  more...
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Overview

Practice Essentials

Key features of fever of unknown origin (FUO), also known as pyrexia of unknown origin (PUO), are as follows:

  • Unexplained fevers are worrisome to patients and clinicians, but most persistent fevers are diagnosed, and often within one week of hospital evaluation or 3 outpatient visits.
  • Most fevers that persist beyond this period are caused by common conditions presenting uncommonly.
  • Hundreds of conditions may cause FUO. While infections remain a significant cause, most FUOs in the developed world are caused by noninfectious inflammatory disorders, with malignancy a much smaller percentage. Infection is likely to evolve with increased global travel and use of immunomodulating drugs.
  • The differential diagnoses of FUO depend on and continue to evolve based on regional factors, exposures, and available diagnostic tools.
  • A significant percentage of FUO cases are caused by miscellaneous conditions, and there is no standard algorithm for evaluating FUO. The approach to diagnostic study is best guided by ongoing assessment for historical, physical, and basic laboratory clues. Following clues and beginning with the least invasive evaluation avoids unnecessary harm and cost to the patient.
  • Physical examination in FUO should pay special attention to skin, eyes, lymph nodes, liver, and spleen.
  • It is reassuring that most cases of FUO that remain undiagnosed despite intensive evaluations have a good long-term prognosis and resolve within a year.
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Background

The syndrome of fever of unknown origin (FUO) was defined in 1961 by Petersdorf and Beeson as the following: (1) a temperature greater than 38.3°C (101°F) on several occasions, (2) more than 3 weeks' duration of illness, and (3) failure to reach a diagnosis despite one week of inpatient investigation. [1, 2] However, it is important to allow for flexibility in this definition. The emergence of human immunodeficiency virus (HIV) and the expanding use of immunomodulating therapies prompted Durack and Street to propose differentiating FUO into four categories: classical FUO (Petersdorf definition), hospital-acquired FUO, immunocompromised or neutropenic FUO, and HIV-related FUO. [3]

Emerging techniques such as molecular diagnostics, expanding use of immunocompromising therapies and organ transplantation, and the advent of globally mobile populations demand an evolving approach to defining and evaluating FUO. [4, 3, 5] Modern imaging techniques (eg, ultrasonography, computed tomography [CT] scanning, magnetic resonance imaging [MRI], positron emission tomography [PET]) enable early detection of abscesses and solid tumors that were once difficult to diagnose.

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Etiology

A baseline definition of "fever" is important in determining whether a patient's report of an elevated temperature warrants an FUO workup. Most temperatures are measured orally for both practical and physiologic purposes. A "normal" core (internal) body temperature ranges from 96º Fahrenheit (F) (35.6º Celsius [C]) to 100.8ºF (38.2ºC) in healthy persons, with a mean of 98.2ºF (36.8ºC). Core temperature in the afternoon is about 1ºF higher later in the day and may be a bit higher in women.

The temperature of the sublingual fossa correlates most closely, and changes most consistently, with core body temperature, which is fairly constant; the rectum and axilla do not, especially during sepsis. The tympanic membrane also correlates with core body temperature and is nearest to the hypothalamic center that regulates temperature, but accuracy depends on user technique and whether the ear canal is obstructed (eg, by wax); cold weather also cools the tympanic membrane. [6]

For the purposes of this article, the term FUO refers to the classic category, which focuses on the adult population. The definition of FUO in the pediatric age group varies, with a time frame ranging from 1-3 weeks in the literature. In this age group, the differential diagnoses are led by infections, followed by collagen vascular diseases; malignancy is typically not heralded by fever alone in children. [7] This article excludes FUO in the setting of impaired immunity such as HIV disease, solid-organ and bone marrow transplantation, and neutropenia. Disease-specific diagnostic algorithms in these conditions are described elsewhere. Regardless of age group, most clinicians define FUO as a persisting conundrum with few or no objective clues.

Causes of FUO may differ geographically based on regional exposures, economic development, and available diagnostic tools. For example, in developing countries, infection may predominate, while noninfectious inflammatory and malignant conditions are more common in developing countries.  The focus of this article is FUO in developing countries; however, travel-associated causes that may present from developing countries should not be missed.

The list of etiologic possibilities is extensive, and it is helpful to break the differential diagnoses into broader categories, such as infection, noninfectious inflammatory conditions, malignancies, and miscellaneous. In recent years, noninfectious inflammatory disorders predominate, with infection now second.

A prospective review of FUO in 290 subjects between 1990 and 1999 found noninfectious inflammatory diseases in 35.2% of cases, infections in 29.7%, miscellaneous causes in 19.8%, and malignancies in 15.1%. Most were diagnosed within 3 visits or 3 hospital days. This differs from prior estimates, in which infections dominated, followed by malignancies, collagen vascular diseases, and numerous miscellaneous conditions. With the increasing use of immunomodulators used to treat an expanding range of conditions, infection may yet regain its lead as the cause of FUO. Interestingly, the rate of unknown causes is higher in this report than in prior estimates, with 33.8% remaining undiagnosed beyond 7 days. The short time frame may overestimate the number of undiagnosed cases. Evaluations in the past may not have proceeded as quickly, and, even now, newer tests may require transport to specialty laboratories, and diagnosis may still take longer than 7 days. [8]

The causes of FUO are often common conditions presenting atypically. Listed below are the most common, less common, and least common in their respective categories, but by no means the only causes.

Noninfectious Inflammatory Causes of FUO (Connective Tissue Diseases, Vasculitides, and Granulomatous Disorders)

The most common noninfectious inflammatory causes of FUO include the following:

  • Giant cell (temporal) arteritis
  • Adult Still disease (juvenile rheumatoid arthritis)

Less-common noninfectious inflammatory causes of FUO include the following:

  • Systemic lupus erythematosus (SLE)
  • Periarteritis nodosa/microscopic polyangiitis (PAN/MPA)
  • Rheumatoid arthritis (RA)

The least common noninfectious inflammatory causes of FUO include the following:

  • Antiphospholipid syndrome (APS)
  • Gout
  • Pseudogout
  • Behçet disease
  • Sarcoidosis
  • Felty syndrome
  • Takayasu arteritis
  • Kikuchi disease
  • Periodic fever adenitis pharyngitis aphthous ulcer (PFAPA) syndrome

Infectious Causes of FUO

The most common infectious causes of FUO include the following:

  • Tuberculosis (TB)
  • Q fever (parturient animals)
  • Brucellosis (hooved mammals, raw dairy)

Less-common infectious causes of FUO include the following:

  • HIV infection
  • Abdominopelvic abscesses
  • Cat scratch disease (CSD)
  • Epstein-Barr virus (EBV) infection
  • Cytomegalovirus (CMV) infection
  • Enteric (typhoid) fever
  • Toxoplasmosis
  • Extrapulmonary TB

The least common infectious causes of FUO are listed below.

Organ-based infectious causes of FUO are as follows:

  • Subacute bacterial endocarditis (SBE)
  • Tooth abscess
  • Chronic sinusitis/mastoiditis
  • Chronic prostatitis
  • Discitis
  • Vascular graft infections
  • Whipple disease
  • Multicentric Castleman disease (MCD)
  • Cholecystitis
  • Lymphogranuloma venereum (LGV)

Geographic and travel-related considerations for FUO are listed below.

Tickborne infections, as follows:

  • Babesiosis, Ehrlichiosis (southeast and central United States)
  • Anaplasmosis (northeast and north central United States)
  • Tickborne relapsing fever (rodent-infested cabins)

Regional infections, as follows:

  • Histoplasmosis (Midwest United States, Ohio and Mississippi River Valleys, Central and South America, bat/bird droppings)
  • Coccidiomycosis (southwest United States)
  • Leptospirosis (tropics, freshwater swimming, triathlons, "mud run" races)
  • Visceral leishmaniasis (Latin America, Middle East)
  • Rat-bite fever (rat bite, food or water)

Malignant and Neoplastic Causes of FUO

Malignant and neoplastic causes of FUO are as follows:

  • Most common: Lymphoma, renal cell carcinoma
  • Less common: Myeloproliferative disorder, acute myelogenous leukemia
  • Least common: Multiple myeloma, breast/liver/pancreatic/colon cancer, atrial myxoma, metastases to brain/liver, malignant histiocytosis

Miscellaneous Causes of FUO

Miscellaneous Causes of FUO are as follows:

  • Most common: Cirrhosis (due to portal endotoxins), drug fever
  • Less common: Thyroiditis, Crohn disease (regional enteritis)
  • Least common: Pulmonary emboli, hypothalamic syndrome, familial periodic fever syndromes, cyclic neutropenia, factitious fever (especially in those experienced with the healthcare field)
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Patient Education

For patient education information, see Fever in Adults and Fever in Children.

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Prognosis

Despite extensive differential diagnoses, patients with FUO that remains undiagnosed after an intensive and rational diagnostic evaluation generally have a reassuringly benign long-term course.

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