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emedicine.medscape.com

Fever of Unknown Origin (FUO)

Updated: Apr 10, 2024
Author: Sandra G Gompf, MD, FACP, FIDSA; Chief Editor: Michael Stuart Bronze, MD

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 1 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.
While there is no specific diagnostic algorithm of benefit, geographic disease prevalence must be considered in
the diagnostic differential.
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.
About 25-50% of cases remain 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.
A study of 132 patients seen in a university FUO clinic from May 2019 to February 2022 found that 40% of
cases remained undiagnosed, but another 31% met criteria for "functional hyperthermia", which they
defined as fever without a physiologic cause and preceded by and resolves upon removal of a
psychological stressor. The authors propose a "functional hyperthermia" as an unrecognized cause of
FUO, postulated due to sympathetic hyperactivity. [31]

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 1 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

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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.

In a meta-analysis of 8 prospective studies of FUO from 1997 to 2021, neither structured nor nonstructured diagnostic
approaches to FUO yielded a significant advantage. However, geographic prevalence and probabilities need to be
factored into any protocol and contributes to improved success.[29]

Etiology
A baseline definition of "fever" is important in determining whether a patient's report of an elevated temperature warrants
a fever of unknown origin (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 typically is 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 also is 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.

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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 still may take longer than 7 days.[15]

The causes of FUO often are 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)

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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)

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

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

Presentation

History
The history can provide important clues to fever of unknown origin (FUO) due to zoonoses, malignancies, and
inflammatory/immune disorders. In adults with FUO, inquire about symptoms involving all major organ systems and
obtain a detailed history of general symptoms (eg, fever, weight loss, night sweats, headaches, rashes). Record all
symptoms, even those that disappeared before the examination. Previous illnesses (including psychiatric illnesses) are
important. Look for patterns of symptoms and relapsing fevers.

Make a detailed history evaluation that includes the following:

Family history
Immunization status
Dental history
Occupational history
Travel history, especially within the prior year
Nutrition and weight history (including consumption of dairy products); note changes in the fit of clothing if the
patient does not monitor weight
Drug history (over-the-counter medications, prescription medications, illicit substances)
Sexual history
Recreational habits
Animal contacts (including possible exposure to ticks and other vectors)
Surgery, invasive procedures, trauma

Fever pattern
Fever with rigors or shaking chills is most suggestive of infection, as opposed to noninfectious inflammatory conditions.

In general, specific fever patterns do not correlate strongly with specific diseases. Notable exceptions include classic
recurrent fevers, as follows:

Tertian fever in prolonged malaria (occurring every third day)

Undulant fever in brucellosis (evening fevers and sweats resolving by morning)
Tick-borne relapsing fever ( Borrelia hermsii, B parkeri, B duttonii; fever lasting 1-3 days followed by up to 2
weeks without fever followed by another 1-3 days of fever) [27]
Louse-borne relapsing fever ( Borrelia recurrentis; fever lasting roughly 3-6 days followed by up to 2 weeks
without fever followed by 1-5 febrile episodes that decrease in severity) [28]
Pel-Ebstein (cyclical) fever in Hodgkin disease (week-long high fevers with week-long remissions)
Periodic fevers in cyclic neutropenia
Double quotidian fever (two fever spikes a day) in adult Still disease; also seen in malaria, typhoid, and other
infections

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Morning fevers in polyarteritis nodosa, tuberculosis, and typhoid

Historical clues to likely noninfectious inflammatory causes of FUO

Collagen vascular and autoimmune diseases can manifest as FUO if the fever precedes other, more specific
manifestations (eg, arthritis, pneumonitis, renal involvement). Weight loss is not unusual.

Clues and etiologic associations are as follows:

Headache, jaw claudication, and visual disturbances (visual loss, blurred vision, diplopia, amaurosis fugax): Giant
cell or temporal arteritis
Symmetrical pain and stiffness of lumbar spine and large proximal muscles (neck, shoulders, hips, thighs):
Polymyalgia rheumatica; also myalgias, tender muscles, lacelike rash (livedo reticularis), testicular pain
High-spiking fevers, nonpruritic morbilliform rash that follows the fever curve, arthralgias: Adult-onset Still
disease, lymphadenopathy
Facial rash: SLE
Right lower quadrant pain, diarrhea (or none): Crohn disease (regional enteritis); Yersinia enteritis may mimic
Crohn disease or appendicitis
Erythema nodosum, painful nodules on shins: Idiopathic erythema nodosum may itself cause fever sarcoidosis;
Crohn disease; ulcerative colitis; Behçet disease
CNS disorders, specifically subarachnoid haemorrhage, cerebral trauma, ischemic or haemorrhagic stroke:
Central fever with disorder of thermoregulation

Historical clues to likely infectious causes of FUO

Clues and etiologic associations are as follows:

Previous abdominal surgery, trauma, or a history of diverticulosis, peritonitis, endoscopy, urologic or gynecologic
procedures: Intraabdominal abscess, perinephric abscess, psoas abscess
Erythema nodosum, painful nodules on shins: Granulomatous fungal infections, histoplasmosis,
coccidioidomycosis, Yersinia enteritis, tuberculosis

Animal and animal product exposures

A history of exposure to unpasteurized dairy (eg, swine, cattle, goats, camels, sheep) may suggest the following:

Brucellosis
Coxiella burnetii ( chronic Q fever, Q fever endocarditis; parturient animals aerosolize Coxiella from the placenta)
Yersinia enterocolitica/ Yersinia pseudotuberculosis: Mesenteric adenitis, pseudoappendicitis, with or without
diarrhea

Exposure to birds (especially new pets, sick birds) may suggest Chlamydia psittaci infection.

Exposure to cats or cat litter may suggest toxoplasmosis or cat scratch disease (especially kittens).

Exposure to undercooked or undersmoked game meats, especially bear, cougar, wild hog, may suggest trichinosis
(diffuse myalgias).

Travel-related and other environmental exposures

Travel-related and other environmental exposures are as follows:

Desert areas of the southwest United States, California: Coccidioides immitis infection
River valleys (Ohio, Mississippi, Central/South America): Histoplasma, Blastomyces infection
Caves (bats): Histoplasma infection
Swimming in rivers, fresh water, especially with rains: Leptospirosis
Rural Central/South America, Africa, Asia: Tuberculosis, especially extrapulmonary; malaria (in malaria-prone
areas; travelers of developed countries may not seek pretravel advice or take malaria prophylaxis; malaria may
manifest weeks to months after return home)
Mediterranean, tropics: Visceral leishmaniasis
United States, rodent-infested cabins: Borrelia hermsii (tick-borne relapsing fever), week-long fevers interrupted
by week-long remissions

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North America, Eurasia, tick-infested brush and forest: Borrelia miyamoto i

Middle East, Latin America, refugees, disrupted civil services in disaster or war, humanitarian aid workers:
Borrelia recurrentis/Brucella melitensis (louse-borne relapsing fever)
Uncertain sanitation, adventurous eating: Salmonella typhi (typhoid)

Sexual encounters without barrier precautions

Travelers are especially likely to experience unanticipated encounters out of their usual norm; consider HIV,
disseminated gonorrhea.

Childcare, daycare, grandchildren

Acute Epstein-Barr virus (EBV) infection is easily spread, and a small percentage of adults are not immune; fever for
several weeks with or without organomegaly may be the only symptom in older adults.

Acute cytomegalovirus (CMV) is similarly easy to acquire and may cause several weeks of fever in adults (reactivation
also is possible, with manifestations in several organ systems).

Acute Parvovirus B19 infection can manifest with fever, arthralgias, rash, fatigue, with fever being one of the most
common symptoms of adults.

Historical clues to malignant causes of FUO

Historical clues to malignant causes of FUO are as follows:

Pel-Ebstein (cyclical) fever in Hodgkin disease (week-long high fevers with week-long remissions)
Lymphadenopathy, painless: Lymphoma, leukemia
Weight loss with anorexia
Itching after a hot bath: Lymphoma
Erythema nodosum, painful nodules on shins: Lymphoma

Historical clues to miscellaneous causes of FUO

Historical clues to miscellaneous causes of FUO are as follows:

Prolonged immobility, car trips, flights: Thromboembolic disease

Ethanol abuse: Alcoholic hepatitis, cirrhosis (endotoxemia of portal circulation)
Medication list review: Drug fever
Anticoagulant use: Hematoma, occult hemorrhage

Physical Examination
Definitive documentation of fever and exclusion of factitious fever are essential early steps in the physical examination.
Measure the fever more than once and in the presence of healthcare personnel to exclude manipulation of
thermometers.

On physical examination, pay special attention to the eyes, skin, lymph nodes, spleen, heart, abdomen, and genitalia.

Repeat a regular physical examination daily while the patient is hospitalized. Pay special attention to rashes, new or
changing cardiac murmurs, signs of arthritis, abdominal tenderness or rigidity, lymph node enlargement, funduscopic
changes, and neurologic deficits.

Physical examination clues to causes of FUO are as follows:

Pulse-temperature deficit or relative bradycardia (inappropriately low pulse rate for degree of fever, in the
absence of beta blockade): Typhoid fever, Q fever, psittacosis, legionellosis, lymphoma, drug fever
Unequal pulse in upper extremities: Takayasu arteritis
Eyes - Roth spots, retinal artery occlusion: SLE, vasculitis, bacterial endocarditis, cat scratch disease (stellate
retinitis)

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Oral ulcers: SLE, Behçet disease, histoplasmosis

Tender tooth on percussion, caries/gingivitis: Dental abscess
Enlarged or tender thyroid: Thyroiditis
Lymphadenopathy: Sarcoidosis, SLE, adult-onset Still disease, granulomatous infections, hematologic
malignancies
Cardiac murmur: SLE (Libman-Sacks endocarditis), bacterial endocarditis
Hepatomegaly without splenomegaly: Granulomatous hepatitis, primary liver cancer, renal cell carcinoma, or liver
metastases; excludes collagen vascular disease and hematologic malignancy
Splenomegaly without hepatomegaly: Bacterial endocarditis, EBV/CMV infection, typhoid, tuberculosis,
histoplasmosis, brucellosis, malaria, Q fever, borreliosis (relapsing fevers), cirrhosis
Tenderness to palpation of sternum: Hematologic malignancy
Tenderness to percussion over a vertebra: Vertebral osteomyelitis, tuberculosis, typhoid, brucellosis
Epididymitis or nodules: Sarcoid, SLE, polyarteritis nodosa
Tender red nodules on shins: Idiopathic erythema nodosum (EN), collagen vascular disease, granulomatous
infections, EBV infection, typhoid, bartonellosis, drug fever

DDx

Diagnostic Considerations
Approximately 5-15% of patients with fever of unknown origin (FUO) remain undiagnosed, even after extensive
evaluations.

Hepatobiliary infections

Acute cholecystitis and gallbladder empyema can lead to a diagnosis of FUO because of the lack of right upper quadrant
pain or jaundice, especially in elderly patients.

Osteomyelitis

The most common reason for misdiagnosis of osteomyelitis is the failure to consider the disease in a patient who is
febrile with musculoskeletal symptoms.

Parasitic infections

If the physician is unaware of a history of recent travel to an endemic area and if the fever pattern is nonsynchronized,
malaria can be missed as a cause of fever.

Drug fever

A history of allergy, skin rashes, or peripheral eosinophilia often is absent in cases of drug fever.

Tuberculosis

Tuberculosis (TB) usually is considered in the differential diagnoses; however, several factors may prevent a prompt
diagnosis of TB. Miliary TB may initially manifest as constitutional symptoms that lack localizing signs.

Collagen-vascular and autoimmune diseases

Consider PAN, RA, and mixed connective-tissue diseases in patients with FUO, because of the potential for nonspecific
presentations in these diseases. Rheumatic fever can be difficult to diagnose, because it is rare in the developed world.

Conditions to consider in the diagnosis of FUO

More than 200 conditions may cause FUO and include the following, as well as the disorders in the Differentials
subsection, below:

Abdominal Abscess

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Actinomycosis

Acute Lymphoblastic Leukemia

Acute Myelogenous Leukemia

Adenoviruses

Adrenal Carcinoma

Adrenal Insufficiency

Amebiasis

Amebic Hepatic Abscesses

Atrial Myxoma

Atypical Mycobacterial Infection

Bacillary Angiomatosis

Bacteroides Infection

Bartonellosis

Blastomycosis

Brain Abscess

Brucellosis

California Encephalitis

Campylobacter Infections

Candidiasis

Carcinoid Tumor, Intestinal

C burnetii infection

Chagas Disease (American Trypanosomiasis)

Cholangitis

Cholecystitis

Choledocholithiasis

Chronic Bacterial Prostatitis

Chronic Lymphocytic Leukemia

Chronic Mesenteric Ischemia

Chronic Myelogenous Leukemia

Clostridial necrotizing fasciitis

Colon Cancer, Adenocarcinoma

Coxsackieviruses

Cryptococcosis

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Cytomegalovirus

Cytomegalovirus Colitis

Dengue Fever

Diabetic Ulcers

Drug Fever

Eastern Equine Encephalitis

Echoviruses

Emphysematous Pyelonephritis

Empyema, Gallbladder

Empyema, Pleuropulmonary

Enteroviruses

Eosinophilic Pneumonia

Eosinophilic Toxocariasis

Epididymal Tuberculosis

Epididymitis

Epidural Abscess

Erythema Multiforme (Stevens-Johnson Syndrome)

Factitious Fever

Gallbladder Gangrene

Gastroenteritis, Viral

Giardiasis

Graves Disease

Hairy Cell Leukemia

Hepatitis A-E

Hepatoma

Herpes Simplex

Histoplasmosis

Human Immunodeficiency Virus

Human Herpesvirus Type 6

Hypersensitivity Pneumonitis

Hyperthyroidism

Inflammatory Bowel Disease

Intra-abdominal Sepsis

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Japanese Encephalitis

Kikuchi Disease

Legionnaires Disease

Leishmaniasis

Leptospirosis

Leukocytoclastic Vasculitis

Libman-Sacks Endocarditis

Listeria Monocytogenes

Liver Abscess

Lung Abscess

Lymphocytic Choriomeningitis

Lyssavirus Infection

Malaria

Malassezia furfur Infection

Malignant histiocytosis

Mastocytosis, Systemic

Mediterranean Fever, Familial

Mediterranean Spotted Fever

Meningococcemia

Miliary Tuberculosis

Mucormycosis

Mycoplasma Infections

Naegleria Infection

Neuroleptic Malignant Syndrome

Nocardiosis

Nonarticular Rheumatism/Regional Pain Syndrome

Nonbacterial Prostatitis

Norwalk Virus

Onchocerciasis

Osteomyelitis

Pancreatitis, Acute

Pelvic Inflammatory Disease

Pericholangitis

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Pharyngitis, Viral

Pneumonia, Viral

Prostatic Abscess

Psittacosis

Q Fever

Rat-bite Fever (S minor)

Rhinocerebral Phycomycosis

SARS-Covid 19

Sphenoid Sinusitis

Thrombophlebitis

Trypanosoma Infection

West Nile Virus

Zika Virus

Differential Diagnoses
Acute Pericarditis

Appendicitis

Arenaviruses

Aspergillosis

Cat Scratch Disease (Cat Scratch Fever)

Celiac Disease (Sprue)

Constrictive Pericarditis

Gout and Pseudogout

Graft Versus Host Disease (GVHD)

Myocarditis

Workup

Workup

Approach Considerations
Laboratory and imaging findings vary according to the source of a fever of unknown origin (FUO). Imaging should be
directed by historical, physical, and basic laboratory clues.[1, 16, 17, 18]

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Laboratory Studies
While a workup of FUO should emphasize clinical clues, the following, if not already performed, are essential laboratory
and imaging tests that are of value in eliciting further diagnostic direction:

Complete blood cell (CBC) count with white blood cell (WBC) differential
Peripheral blood smear
Complete metabolic panel (CMP; provides data on electrolytes, glucose, acid-base, renal, liver, protein status)
C-reactive protein (CRP)
Erythrocyte sedimentation rate (ESR)
Urinalysis (used to detect glomerulonephritis, occult hematuria; pyuria is insensitive for detecting urinary tract
infection in the absence of suggestive symptoms, as asymptomatic bacteriuria is common) [19]
Blood cultures, preferably 3 blood draws from separate sites, performed at different times
HIV serology
Hepatitis A and B serology, and if epidemiologically applicable, Hepatitis E serology
Tuberculosis screening tests – Purified protein derivative (PPD, or Mantoux test); interferon gamma release
assays (IGRA)
Posteroanterior and lateral chest radiography

Beyond the above essentials in early screening, some would add antinuclear antibody titers, rheumatoid factor, and
thyroid stimulating hormone (TSH) and thyroxine level in diagnosing certain conditions (lupus, RA, thyroiditis,
hyperthyroidism). Their diagnostic accuracy is limited in other autoimmune and collagen vascular diseases.

Further examinations should be guided by historical and physical diagnostic clues, as well as clues from the initial results
of the above.

HIV serology
If any test should be routinely included in the evaluation of FUO, HIV antigen-antibody assay should. Antigen-antibody
assay results are positive early in infection, thus eliminating need for HIV viral load screening because of lag in antibody
seroconversion.

C-Reactive Protein

Elevated CRP suggests an infectious or inflammatory process, but does not eliminate malignancy.

Erythrocyte sedimentation rate

An ESR of more than 100 seconds in the absence of anemia may indicate giant cell arteritis, multiple myeloma, or
osteomyelitis.

A very low ESR with myalgias suggests trichinosis.

Complete blood count

Eosinophilia may suggest polyarteritis nodosa, drug fever, or visceral leishmaniasis.

Acute drop in hemoglobin or hematocrit may suggest occult hemorrhage or hematoma (often retroperitoneal).

Complete metabolic profile

Alkaline phosphatase elevation suggests lymphoma or granulomatous hepatitis.

Transaminitis may result from multiple causes.

Elevated total protein or calcium (look for monoclonal gammopathy) may suggest multiple myeloma.

Urinalysis

Hematuria may indicate renal cell carcinoma, tuberculosis, endocarditis, brucellosis, lymphoma, or periarteritis nodosa.

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Asymptomatic pyuria and bacteriuria are common with advancing age and comorbidities, and these findings may offer
little diagnostic direction.[19]

Normal urinalysis or urine culture results do not necessarily suggest or eliminate perinephric abscess. Approximately
30% of patients with perinephric abscess have normal urinalysis results, and up to 40% have sterile urine cultures.[20]

Blood cultures

Blood cultures for aerobic and anaerobic pathogens are essential in the evaluation; however, no more than 6 sets of
blood cultures are required. Sampling 2-3 peripheral blood samples may suffice given modern culture techniques.

Tuberculosis screening

PPD or Mantoux screening is inexpensive and sensitive but requires placement by clinical staff and interpretation 48-72
hours later of induration size, a type IV hypersensitivity reaction (indicating prior tuberculosis exposure).

Interferon gamma release assay (IGRA) offers higher sensitivity and, where readily available and quickly processed,
faster turnaround.

Laboratory clues to specific causes of FUO

Anemia is an important finding and suggests a serious underlying disease.

Suspect herpesvirus infection if the patient has lymphocytosis with atypical cells.

Leukocytosis with an increase in bands suggests an occult bacterial infection, as well as occult hemorrhage, hematoma,
or thromboembolic process.

Diagnose malaria and spirochetal diseases with the aid of direct examination of the peripheral blood smear; however,
repeated examinations by an experienced technologist are often necessary. With relapsing fever/spirochetal diseases, it
is best to obtain blood sample during febrile period for highest probablity of spirochetemia and direct observation.
Preleukemic states may not manifest in the peripheral blood smear, and bone marrow aspirate may not reveal the
correct diagnosis; bone marrow biopsy may be necessary for diagnosis.

Adult-onset Still disease often is difficult to diagnose. Laboratory abnormalities include pronounced leukocytosis, an
elevated erythrocyte sedimentation rate (ESR), anemia, and abnormal liver function test results.

Among solid tumors, renal cell carcinoma is most commonly associated with FUO, with fever being the only presenting
symptom in 10% of cases. Hematuria may be absent in approximately 40% of cases, whereas anemia and a highly
elevated sedimentation rate are common.

Laboratory findings in giant cell arteritis (GCA) include an elevated ESR, mild to moderate normochromic normocytic
anemia, elevated platelet counts, and abnormal liver function test results (25% of cases). Perform a biopsy of a temporal
artery to obtain a definitive diagnosis. Pathologic review shows vasculitis and a mononuclear cell infiltrate.

At least one liver function test result usually is abnormal in an underlying disease that originates in the liver or a disease
that causes nonspecific alterations of the liver (eg, granulomatous hepatitis).

Tissue analysis and cultures

See Procedures.

Assays, serology, and cultures

Aside from HIV screening, other assays, serology, and cultures should be directed by findings of the history, physical,
and laboratory screening, as well as clinical reevaluation for more diagnostic clues. The specifics of testing for individual
conditions is deferred to other more detailed sources.

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Imaging Studies
Chest radiography

Routinely perform chest radiography. Posteroanterior and lateral chest radiography usually is readily available and
relatively inexpensive. It may rapidly detect abnormalities missed on physical examination, and may direct further
diagnostic imaging with computed tomography (CT) of the thorax.

Thoracic CT angiography

Thoracic CT angiography is more sensitive than ventilation-perfusion scanning when pulmonary emboli are suspected in
spite of negative findings on venous ultrasonography of the extremities. Arteriography demonstrates small and large
aneurysms and focal constrictions between dilated segments in polyarteritis nodosa.

Echocardiography

Echocardiography is highly sensitive in diagnosing endocarditis, particularly when transesophageal echocardiography is

available. Culture-negative endocarditis is reported in 5-10% of endocarditis cases. Prior antibiotic therapy is the most
common reason for negative blood culture results.

CT scanning of the abdomen and pelvis

CT scanning of the abdomen and pelvis with intravenous and oral contrast is useful in the setting of hepatosplenomegaly
looking for adenopathy, intraabdominal or psoas muscle hematoma or abscess, perinephric abscess, cholecystitis, or
neoplasia. Plain abdominal films and ultrasonography are relatively insensitive in the diagnosis of FUO. In patients with
hepatobiliary infections, cholangitis can occur without local signs and with only mildly elevated or normal findings on liver
function tests.

FDG-PET/CT whole-body scanning

Positron emission tomography (PET) scanning alone once was fraught with excessive false-positive findings; however,
PET combined with CT improves diagnostic capabilities, especially as the causes of FUO have evolved in the past
decade. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), in which radiolabeled glucose marks foci of
increased glucose metabolism, has been used successfully in oncology diagnostics and also can be used to diagnose
infectious and noninfectious inflammatory foci. Recent studies recommend using FDG-PET early in the workup of FUO
and suggest that including FDG-PET/CT yields a correct diagnosis in 60% to more than 80% of cases. Furthermore, the
time to diagnosis may be shortened and invasive procedures reduced, potentially leading to reduced costs and
morbidity. Nonetheless, the possibility of false-positive results should be kept in mind.[9, 21, 22, 23]

Radionucleotide studies

Radionucleotide studies using gallium citrate are used to detect chronic inflammation and may be more sensitive in
detecting occult abscesses, neoplasms, or soft-tissue lymphomas in FUO of more than 2 weeks’ duration. Indium WBC
scan, using granulocytes labeled with indium In 111 (111In), can be cumbersome and often insensitive in chronic
inflammatory states.

Bone scanning

Whereas plain radiographs may not show changes for weeks after the onset of infection, technetium bone scan may be
a more sensitive method for documenting skeletal involvement when osteomyelitis is suspected. Magnetic resonance
imaging (MRI) is considered the criterion standard for detection of acute osteomyelitis and delineating structural
abnormalities; however, it is less sensitive in the setting of chronic osteomyelitis and prosthetic joint infection. While
potentially a greater cost upfront, positron emission tomography-computed tomography (PET-CT) full-body scans are
increasingly recognized as useful early in efficiently localizing abnormalities and may save other healthcare costs in the
FUO workup. PET-CT is especially sensitive in localizing and detecting small foci of inflammation and metabolic activity.
It is particularly superior to MRI and other nuclear imaging studies in localizing foci of osteomyelitis of the hip, vertebrae,
or prosthetic devices, as well as endovascular graft infection, neoplasia, and vasculitides.[22, 24]

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Other Tests
Naproxen test

Simple, noninvasive, and inexpensive, a naproxen test may rapidly screen out infection versus neoplastic disease and
significantly narrow the differential diagnoses. In this test, naproxen sodium 250 mg is given orally every 8 hours for 3
days. A sharp decline or resolution in fever within 24 hours directs the workup away from infection and suggests a
neoplastic disorder.

Procedures
FUO evaluations are best performed from least invasive to more invasive testing.

Endoscopy

Perform an endoscopic examination of the upper and lower gastrointestinal tract, including retrograde cholangiography
when indicated or when searching for Crohn disease, Whipple disease, biliary tract disease, and gastrointestinal tumors.
Crohn disease is the most common gastrointestinal cause of FUO. Diarrhea and other abdominal symptoms
occasionally are absent, particularly in young adults.

Biopsies and tissue sampling

Obtain cultures for bacteria, mycobacteria, and fungi in all normally sterile tissues and liquids that are biopsied. This may
include cerebrospinal fluid (CSF), pleural or peritoneal fluid, and fluid from the liver, bone marrow, and lymph nodes.

Biopsies are easily performed in enlarged accessible lymph nodes, other peripheral tissues, and bone marrow.
Superficial enlarged lymph nodes of highest yield on biopsy include posterior cervical, supraclavicular or infraclavicular,
and epitrochlear nodes. Deep nodes of highest yield are the hilar, mediastinal, or retroperitoneal lymph nodes.[25]

Bone marrow biopsy is of highest yield with unexplained abnormality of the CBC count (hematologic malignancy) and
granulomatous disease such as sarcoidosis, tuberculosis, or histoplasmosis.[25]

Liver biopsy rarely yields helpful data in patients without abnormal liver function test results or abnormal liver findings
(observed on CT scan or ultrasonography). Liver biopsy may be necessary to characterize granulomatous or
autoimmune hepatitis.

The decision to biopsy is more difficult if it entails an exploratory surgical procedure (eg, laparotomy).[26] This is rarely
indicated (eg, when imaging techniques are nondiagnostic and an intra-abdominal source is suspected), particularly
considering the generally benign course of FUO that remains undiagnosed after extensive workup.

Arterial biopsy rarely is associated with hematoma, ischemic complications, or nerve damage, given that nerves and
vessels often follow a similar course. This may be warranted, however, for the diagnosis of polyarteritis nodosa and giant
cell arteritis, as these conditions may be disabling or life-threatening if left untreated; these are among the few conditions
associated with an erythrocyte sedimentation rate of 100 mm/hour or greater. Biopsy of small- or medium-sized arteries
demonstrate white blood cell infiltrate in polyarteritis nodosa. Temporal artery biopsy is necessary for definitive diagnosis
of giant cell arteritis, provided a sufficient length of artery is excised.

Treatment

Approach Considerations
In general, empiric therapy has little or no role in cases of classic fever of unknown origin (FUO).

Treatment should be directed toward the underlying cause, as needed, once a diagnosis is made.

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Some studies suggest a few exceptions to this general approach, including the following:

Cases that meet criteria for culture-negative endocarditis

Cases in which findings or the clinical setting suggests cryptic disseminated TB (or, occasionally, other
granulomatous infections)
Cases in which temporal arteritis with vision loss is suspected

Several studies have found that prolonged undiagnosed FUO generally carries a favorable prognosis.

Because of a better understanding of the etiologies and careful diagnostic approaches, patients with FUO rarely need
surgical treatment.

Specific examples of treatment

In patients with hepatic granulomas, approximately 50% of patients recover spontaneously, whereas the other 50%
respond to corticosteroid treatment (duration of therapy ranging from a few weeks to several years).

Patients with giant cell arteritis should be treated with high doses of steroids, and intravenous steroids should be
administered if the patient is very ill or has significant ocular compromise. Carefully monitor the patient, since inadequate
treatment and steroid toxicities (eg, hypertension, diabetes, dyspepsia, bone loss, psychosis, cataracts) can cause
significant morbidity.

In polymyalgia rheumatica, the treatment consists of amelioration of symptoms with steroid therapy and close monitoring
for possible development of GCA.

When drug fever is suspected, discontinue the implicated drug. Stopping the causative drug generally leads to
defervescence within 2 days.

Inpatient Treatment
No evidence supports prolonged hospitalization of patients who are clinically stable and whose workup findings are
unrevealing.

Outpatient Care
Conduct close follow-up procedures and systematic reevaluation studies to prevent clinical worsening. Guide further
workup studies on an outpatient basis.

Patient Transfer
The need for transfer is indicated if (1) the current facility is unable to establish a diagnosis, (2) diagnostic tests are
unavailable at the existing facility, or (3) the patient deteriorates clinically such that necessary level of care or
consultations is unavailable.

Consultations
Appropriate consultations are indicated based on patient history, physical examination, laboratory data, and radiologic
findings. Consultations include the following:

Infectious disease specialist

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Hematologist/oncologist
Rheumatologist
Pulmonologist
Gastroenterologist
Endocrinologist
Interventional radiologist
Surgeon

Long-Term Monitoring
The 5-15% of patients whose FUO remains undiagnosed, even after extensive evaluations, usually have a benign long-
term course, but close follow-up and systematic reevaluation studies are essential to avoid missing potential etiologies.

Medication

Medication Summary
The choice of medications administered to patients depends on the etiology of the fever of unknown origin (FUO).

Questions & Answers

Overview

What are key features of fever of unknown origin (FUO)?

How is the syndrome of fever of unknown origin (FUO) defined?

How is fever defined in fever of unknown origin (FUO)?

How are the conditions of the differential diagnosis of fever of unknown origin (FUO) categorized?

How common is the etiology of fever of unknown origin (FUO) identified as a noninfectious inflammatory disease?

What are noninfectious inflammatory causes of fever of unknown origin (FUO)?

What are common infectious inflammatory causes of fever of unknown origin (FUO)?

What are less common infectious causes of fever of unknown origin (FUO)?

What are malignant and neoplastic causes of fever of unknown origin (FUO)?

What are miscellaneous causes of fever of unknown origin (FUO)?

What are patient education resources for fever of unknown origin (FUO)?

What is the prognosis of fever of unknown origin (FUO)?

Presentation

Which symptoms suggest a malignant cause of fever of unknown origin (FUO)?

What should be the focus of history for fever of unknown origin (FUO)?

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What should be evaluated in the history for fever of unknown origin (FUO)?

How do fever patterns help in the identification of the etiology of fever of unknown origin (FUO)?

Which symptoms suggest a noninfectious inflammatory cause of fever of unknown origin (FUO)?

Which symptoms suggest an infectious inflammatory cause of fever of unknown origin (FUO)?

Which etiologies of fever of unknown origin (FUO) are suggested by a history of specific animal exposures?

Which etiologies of fever of unknown origin (FUO) are suggested by travel-related or environmental exposures?

When should HIV or gonorrhea be considered as the etiology of fever of unknown origin (FUO)?

Which history may suggest a viral etiology for fever of unknown origin (FUO)?

Which symptoms suggest a miscellaneous cause of fever of unknown origin (FUO)?

What are the initial steps in the physical exam of fever of unknown origin (FUO)?

Which physical findings suggest specific causes of fever of unknown origin (FUO)?

DDX

What are diagnostic considerations for tuberculosis in fever of unknown origin (FUO)?

How often does fever of unknown origin (FUO) remain undiagnosed?

What are diagnostic considerations for hepatobiliary infections in fever of unknown origin (FUO)?

What are diagnostic considerations for osteomyelitis in fever of unknown origin (FUO)?

What are diagnostic considerations for parasitic infections in fever of unknown origin (FUO)?

What are diagnostic considerations for a drug-related fever of unknown origin (FUO)?

What are diagnostic considerations for collagen-vascular and autoimmune diseases in fever of unknown origin (FUO)?

Which conditions may cause fever of unknown origin (FUO)?

What are the differential diagnoses for Fever of Unknown Origin (FUO)?

Workup

What is the basis for selection of diagnostic tests in fever of unknown origin (FUO)?

What is the role of lab studies in the workup of fever of unknown origin (FUO)?

What is the indication for an HIV serology test in the workup of fever of unknown origin (FUO)?

What is the role of erythrocyte sedimentation rate (ESR) in the workup of fever of unknown origin (FUO)?

What is the role of a complete blood cell (CBC) count in the workup of fever of unknown origin (FUO)?

What is the role of a complete metabolic profile in the workup of fever of unknown origin (FUO)?

What is the role of urinalysis in the workup of fever of unknown origin (FUO)?

What is the role of blood cultures in the workup of fever of unknown origin (FUO)?

What is the role of tuberculosis screening in the workup of fever of unknown origin (FUO)?

Which lab findings suggest a specific cause for fever of unknown origin (FUO)?

How should assays, serology, and cultures be selected for the workup for fever of unknown origin (FUO)?

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What is the role of chest radiography in the workup of fever of unknown origin (FUO)?

What is the role of CT angiography in the workup of fever of unknown origin (FUO)?

What is the role of echocardiography in the workup of fever of unknown origin (FUO)?

What is the role of CT scanning in the workup of fever of unknown origin (FUO)?

What is the role of positron emission tomography (PET) scanning in the workup of fever of unknown origin (FUO)?

What is the role of radionucleotide studies in the workup of fever of unknown origin (FUO)?

What is the role of bone scanning in the workup of fever of unknown origin (FUO)?

What is the role of a naproxen test in the workup of fever of unknown origin (FUO)?

What is the role of endoscopy in the workup of fever of unknown origin (FUO)?

What is the role of biopsies and tissue sampling in the workup of fever of unknown origin (FUO)?

Treatment

What are the treatment options for fever of unknown origin (FUO)?

What are the specific examples of treatment for fever of unknown origin (FUO)?

When is inpatient treatment indicated for fever of unknown origin (FUO)?

How is fever of unknown origin (FUO) managed?

What is the indication for transfer in patients with fever of unknown origin (FUO)?

Which specialist consultations are needed for the treatment of fever of unknown origin (FUO)?

What long-term monitoring is needed for fever of unknown origin (FUO) that remains undiagnosed?

Medications

How are medications for fever of unknown origin (FUO) selected?

Contributor Information and Disclosures

Author

Sandra G Gompf, MD, FACP, FIDSA Professor of Infectious Disease and International Medicine, University of South
Florida Morsani College of Medicine; Chief, Infectious Diseases Section, Director, Occupational Health and Infection
Control Programs, James A Haley Veterans Hospital

Sandra G Gompf, MD, FACP, FIDSA is a member of the following medical societies: American College of Physicians,
Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Coauthor(s)

Michele Davis, MD Fellow in Infectious Disease, University of South Florida Morsani College of Medicine; Co-
Investigator, Florida Department of Health-Hillsborough County

Disclosure: Nothing to disclose.

Alberto Contreras, MD Fellow in Infectious Diseases, University of South Florida Morsani College of Medicine

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 23:37 10/8/24

Alberto Contreras, MD is a member of the following medical societies: HIV Medicine Association, Infectious Diseases
Society of America

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of
Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Charles V Sanders, MD Edgar Hull Professor and Chairman, Department of Internal Medicine, Professor of
Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine in New Orleans; Medical
Director, Medicine Hospital Center, Charity Hospital and Medical Center of Louisiana at New Orleans; Consulting Staff,
Ochsner Medical Center

Charles V Sanders, MD is a member of the following medical societies: Alliance for the Prudent Use of Antibiotics, Alpha
Omega Alpha, American Association for Physician Leadership, American Association for the Advancement of Science,
American Association of University Professors, American Clinical and Climatological Association, American College of
Physicians, American Federation for Medical Research, American Geriatrics Society, American Lung Association,
American Medical Association, American Society for Microbiology, American Thoracic Society, American Venereal
Disease Association, Association for Professionals in Infection Control and Epidemiology, Association of American
Medical Colleges, Association of American Physicians, Association of Professors of Medicine, Infectious Disease
Society for Obstetrics and Gynecology, Infectious Diseases Society of America, Louisiana State Medical Society,
Orleans Parish Medical Society, Royal Society of Medicine, Sigma Xi, The Scientific Research Honor Society, Society of
General Internal Medicine, Southeastern Clinical Club, Southern Medical Association, Southern Society for Clinical
Investigation, Southwestern Association of Clinical Microbiology, The Foundation for AIDS Research

Disclosure: Receives royalties from Baxter International for: Takeda-receives royalties; UpToDate-receives royalties.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf
Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of
the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of
Physicians, London

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of
Physicians, American Medical Association, Association of Professors of Medicine, Infectious Diseases Society of
America, Oklahoma State Medical Association, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Kirk M Chan-Tack, MD Medical Officer, Division of Antiviral Products, Center for Drug Evaluation and Research, Food
and Drug Administration

Disclosure: Nothing to disclose.

John Bartlett, MD † Professor Emeritus, Johns Hopkins University School of Medicine

John Bartlett, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Clinical
Pharmacology, American College of Physicians, American Society for Microbiology, American Society of Tropical
Medicine and Hygiene, American Thoracic Society, American Venereal Disease Association, Association of American
Physicians, Infectious Diseases Society of America, Society of Critical Care Medicine

Disclosure: Nothing to disclose.

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