Fever of Unknown Origin (FUO)

Updated: May 17, 2021
  • Author: Sandra G Gompf, MD, FACP, FIDSA; Chief Editor: Michael Stuart Bronze, MD  more...
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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.
  • The upper limit of normal temperature in healthy outpatients and nonsurgical inpatients is 99.9º Fahrenheit (F) or 39º Celsius (C).
  • Hundreds of conditions may cause FUO. Although 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 the 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, 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 good long-term prognoses and resolve within a year.
  • Historically, about 25-30% of cases remained undiagnosed despite extensive workup. A prospective multicenter study of cases from 2003 to 2005 in the Netherlands reported 51% of cases without a final diagnosis. [1]  A systematic review of 18 papers published from 2005 to 2015 from regions across the globe found a lack of diagnostic outcome in 23%. [2]  In light of considerable advances in diagnostics, this number seems surprisingly high and consistent. 


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. [3, 4]  It is important to allow for flexibility in this definition, however. "Normal" core temperature in studies in developed nations has declined since the Industrial Revolution and may be inferred to peak at 99.9º F (37.7º C). [5, 6]  The emergence of the human immunodeficiency virus (HIV) and the expanding use of immunomodulating therapies prompted Durack and Street to propose differentiating FUO into 4 categories: classical FUO (Petersdorf definition), hospital-acquired FUO, immunocompromised or neutropenic FUO, and HIV-related FUO. [7]

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. [7, 8, 9] 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.



A baseline definition of "fever" is important in determining whether a patient's report of an elevated temperature warrants an FUO workup. The common assumption that "fever" is a temperature over 100.4 F (38 C) is obsolete. Large reviews of nonsurgical patients indicate that average temperature in uninfected individuals has been on the decline since the 1800s and ranges from 95.8 to an upper limit of 99.9 degrees Fahrenheit in both outpatients and inpatients. This may reflect multiple conditions, such as better sanitation and hygiene leading to reduced chronic diseases such as tuberculosis and gingivitis and increases in indoor and air-conditioned activities. Older individuals tend toward cooler temperatures. Most temperatures are measured orally for both practical and physiologic purposes. A "normal" core (internal) body temperature ranges from 96º F (35.6º C) to 99.9ºF (38ºC) in healthy persons. Core temperature in the afternoon is about 1ºF higher later in the day and may be a bit higher in women.  [5, 6]

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.  It is important to recognize that the use of infrared non-contact thermometers in adults may be fraught with error due to variations in user technique, known variations in detection range of these instruments, and environmental temperatures. The tympanic membrane correlates with core body temperature and is nearest to the hypothalamic center that regulates temperature, but accuracy is affected by user technique and whether the ear canal is obstructed (eg, by wax); cold weather also cools the tympanic membrane. [10]   Both temporal artery and forehead thermometers are likely to underestimate core body temperature and should be verified with sublingual or other method if fever is suspected. In the author's 12-month  institutional experience with entrance screening during the COVID-19 pandemic, infrared forehead thermometry results were highly variable and of low yield in detected infected individuals. [11, 12, 13]

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, infections lead the differential diagnoses, followed by collagen vascular diseases; malignancy is typically not heralded by fever alone in children. [14] 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.

Realistically, it is difficult to define a set time frame or defined list of examinations to be performed before declaring "FUO". The duration of unsuccessful diagnosis varies widely because the diagnostic approach to fever is highly dependent upon the tools accessible in a given healthcare setting, including socioeconomic, and other disparities in healthcare. Similarly, local geography and epidemiology factor into diagnostics.

How aggressive and prolonged the evaluation must be before declaring failure is also subjective and dependent on the setting. Reflecting this, Fusco et al found only 6 series out of 18 publications from across the globe predefined a minimum diagnostic workup. "In general, complete blood count, routine haematochemical tests, inflammatory indexes, including C-reactive protein and/or Erythrocyte Sedimentation Rate, urine analysis, blood and urine cultures, chest x-ray and abdominal and pelvic ultrasonography, were included."  [2]

Thus, declaring a case an FUO realistically depends on the standard-of-care approach to fever in a given geographic area or population. 

Causes of FUO may differ geographically based on regional exposures, economic development, and available diagnostic tools. For example, in developing countries, the baseline incidence of infection may be higher, whereas noninfectious inflammatory and malignant conditions are more common in developed countries.  

This article addresses FUO as approached from the lens of practitioners in developed countries; however, causes that may present from developing countries should not be missed and may be increasing with travel. Fusco et al observed the correlation of infections causing FUO in lower-medium income countries, versus neoplasias and non-infectious inflammatory diseases in higher-income nations in a systematic review of 18 case series.  The majority of papers originated from countries considered high (6 countries) and upper-medium (8 countries) income. Four papers originated from Europe, 8 from Asia, and 6 from the Middle East. The final etiologies across the board were infections (nearly 40%), inflammatory diseases (20%), neoplasia (11%), and other (6.5%).  [2]

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. 

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, infections may yet regain their 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. [15]

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)
  • Louse-borne relapsing fever (East African migrants, refugee camps)

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)

Patient Education

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



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.