INTRODUCTION — Clinicians commonly refer to a febrile illness without an initially obvious etiology (sometimes called fever without localizing signs) as fever of unknown origin (FUO). This usage is not accurate. Most febrile illnesses either resolve before a diagnosis can be made or develop distinguishing characteristics that lead to a diagnosis. FUO refers to a prolonged febrile illness without an established etiology despite intensive evaluation and diagnostic testing.
Large case series of FUO have been collected over a number of decades; these facilitate an approach to patients with FUO and an understanding of the changing patterns of FUO with time and newer diagnostic techniques.
The definitions and special populations with FUO as well as the diagnostic approach to the adult with this problem are reviewed here. A specific discussion of the common and uncommon entities causing FUO and the approach to children with FUO is presented separately. (See "Etiologies of fever of unknown origin in adults" and "Fever of unknown origin in children: Evaluation".)
DEFINITION — The definition of FUO derived by Petersdorf and Beeson in 1961 from a prospective analysis of 100 cases has long been the clinical standard :
●Fever higher than 38.3ºC on several occasions
●Duration of fever for at least three weeks
●Uncertain diagnosis after one week of study in the hospital
Refinements to the definition have been proposed, including eliminating the in-hospital evaluation requirement because of the increased expense of inpatient care and sophistication of outpatient evaluation . Expansion of the definition has also been suggested to include health care-associated, neutropenic, and HIV-associated fevers that may not be as prolonged [12,13].
Establishing that a patient has an FUO — As noted above, the degree and duration of fever are not the only criteria for defining an FUO. Prior to concluding that a patient has an FUO, the following evaluation should have been performed and should have been unrevealing:
●Complete blood count, including differential and platelet count
●Blood cultures (three sets drawn from different sites with an interval of at least several hours between each set; in cases in which antibiotics are indicated, all blood cultures should be obtained before administering antibiotics)
●Routine blood chemistries, including liver enzymes and bilirubin
●If liver tests are abnormal, hepatitis A, B, and C serologies
●Urinalysis, including microscopic examination, and urine culture
If any signs or symptoms point to a particular organ system, further testing, imaging, and/or biopsy should be pursued.
ETIOLOGY — Three general categories of illness account for the majority of "classic" FUO cases and have been consistent through the decades. These categories are:
●Systemic rheumatic diseases (eg, vasculitis, rheumatoid arthritis)
●The fraction of undiagnosed FUOs dropped from over 75 percent in the 1930s to less than 10 percent in the 1950s. Since then, the fraction of FUOs that go undiagnosed has steadily increased (figure 1) [4,7,14-16].
●The early FUO series included few systemic rheumatic diseases, illnesses whose characterization has benefited from careful clinical studies, and developments in immunology.
●Extrapulmonary tuberculosis, solid tumors, and abdominal abscesses are now less prevalent causes due to earlier diagnosis by radiologic imaging, particularly computed tomography, and minimally invasive biopsies.
●Exploratory laparotomy has given way to imaging and percutaneous-guided biopsies for diagnosis.
●Infective endocarditis, once a frequent cause of FUO, has become a less common cause with improved techniques for the isolation of organisms. In the current era, when endocarditis is ultimately diagnosed in a patient with FUO, it is more likely to be culture negative or caused by difficult-to-isolate organisms, such as Bartonella quintana. (See "Detection of bacteremia: Blood cultures and other diagnostic tests".)
True FUOs are uncommon. This was illustrated in a report from the Netherlands in which only 73 patients were identified between December 2003 and July 2005 at a 950-bed academic referral hospital and five community hospitals comprising 2800 hospital beds . The authors excluded immunocompromised patients, such as those with AIDS, hypogammaglobulinemia, granulocytopenia, and glucocorticoid therapy. The following distribution of causes was noted:
●Systemic rheumatic disease (eg, vasculitis, systemic lupus erythematosus, polymyalgia rheumatica) – 22 percent
●Infection – 16 percent
●Malignancy – 7 percent
●Miscellaneous – 4 percent
●No diagnosis – 51 percent
Future advances in microbial diagnosis through gene amplification methods and clarification of the pathogenesis of systemic rheumatic diseases will continue to change the distribution of FUO.
Practice advances have not always been helpful in diagnosing FUO. The frequent use of empiric antimicrobials, for example, can delay the diagnosis of some occult abscesses and infections and increases the number of drug fevers. Aggressive immunosuppressive regimens, increased exposure to potentially allergenic medications, lengthy intensive care unit admissions, and the increase in multiresistant organisms as resident hospital flora have all altered the types of FUO’s encountered.
Geography — Infectious causes of prolonged fever in resource-limited countries include tuberculosis, typhoid, amebic liver abscesses, and AIDS. Ease of travel has the potential to bring back to the United States and other resource-rich countries more geographically restricted illnesses that may not be familiar to clinicians, such as malaria, brucellosis, kala azar, filariasis, schistosomiasis, African tick bite fever, relapsing fever, Q fever, dengue virus, chikungunya virus, Zika virus, or Lassa fever [17,18]. (See "Evaluation of fever in the returning traveler".)
The classic geographic distribution of some United States zoonoses is also changing, owing to environmental changes such as incursion by humans into formerly unpopulated areas and global warming. Zoonoses like babesiosis, ehrlichiosis, anaplasmosis, and Lyme disease may present as FUOs in new ecologic niches.
Illnesses contracted abroad may have incubation periods that extend for months; some infections remain latent for years and may therefore present as fevers remote from the time of travel. Individuals traveling may also become infected with organisms to which local residents are not vulnerable because of pre-existing immunity .
Despite the wide variety of exotic diseases, the most common infections among series of FUOs have not changed over the past half century. These continue to include typhoid fever, tuberculosis, amebic abscesses, and malaria. Fever of unknown origin is more often caused by an atypical presentation of a common entity than by a rare disorder.
Subpopulations — Different entities figure in the etiology of FUO based upon features of the population being studied.
Age — The causes of FUO vary dramatically with age. In a series of 100 children with FUO, for example, one-third were self-limited undefined viral syndromes . In contrast, multisystem diseases such as systemic rheumatic diseases (including polymyalgia rheumatica, giant cell arteritis, and other vasculitides) and sarcoidosis accounted for 31 percent of cases in a review of patients with FUO over the age of 65 . Infections accounted for 25 percent and neoplasms 12 percent of cases in this report.
AIDS — The causes of FUO in HIV-infected patients reflect the degree of immunosuppression, best measured by CD4 counts and viral load determinations . Acute HIV infection can present as an FUO when telltale symptoms and signs (rash and diffuse adenopathy) are absent. In one series of 79 episodes of FUO among HIV-infected patients with CD4 counts ranging from 0 to 790/microL and a median of 40/microL, 79 percent were due to infections and 8 percent to malignancies; only 9 percent had no definite diagnosis . Over one-half were due to mycobacteria, two-thirds of which were atypical, most commonly Mycobacterium avium complex (MAC). Only lymphomas were highly represented among malignancies, particularly non-Hodgkin lymphomas. Disseminated Kaposi's sarcoma was relatively infrequent. A similar distribution was noted in another report of 59 HIV-infected patients .
As with FUO in HIV-uninfected patients, the country in which the study is performed influences the prevalent etiologies detected. In one study from Spain, for example, 137 HIV-infected patients with fevers for at least 10 days and no diagnosis after 1 week in hospital underwent bone marrow biopsy . The three most common diagnoses were mycobacterial infection (18 patients with Mycobacterium tuberculosis and 14 with MAC), non-Hodgkin lymphoma, and visceral leishmaniasis. (See "Fever and rash in patients with HIV".)
Neutropenia — Neutropenia-associated febrile episodes without a source are most frequently linked to bacteremia. Fungal infections replace bacterial infections in prominence after the acute period (after seven days) .
Fever of unknown origin in this population is particularly confounding. It occurs in the context of a serious underlying condition that may itself cause fever. In addition, patients are often taking a number of medications (including antimicrobials), are receiving blood products, have varying degrees of immunosuppression, and, in transplant recipients, may experience allograft rejection. Finally, febrile neutropenia usually mandates empirical antimicrobial therapy, which may confound the subsequent detection of bacterial infections. (See "Overview of neutropenic fever syndromes".)
Fever, even if unexplained, usually abates with return of neutrophils. When fever persists or returns after the patient is no longer neutropenic, hepatosplenic candidiasis should be strongly considered . (See "Chronic disseminated candidiasis (hepatosplenic candidiasis)".)
DIAGNOSTIC APPROACH — The most critical feature of the evaluation of a patient with FUO is to take a careful history and to reassess the patient frequently. It is important to look for uncommon presentations of common diseases and to perform a detailed physical examination.
History and physical examination — The history and physical examination, like laboratory tests, have the potential to generate valuable diagnostic clues in patients with FUO. The art of diagnosis is one of discrimination, as the clinician must determine which data to glean and which clues to pursue. In the series of 73 patients from the Netherlands cited above, the authors found an average of 10.5 potential diagnostic clues per patient through their careful history and physical examination and three per patient through laboratory testing . Eighty-one percent of these clues were misleading.
A thorough history should include the following information:
●Animal exposure (eg, pets, occupational, living on a farm)
●Immunosuppression (with the degree noted)
●Drug and toxin history, including antimicrobials
Subtle findings may be elicited through a careful history. Examples include subtle changes in behavior or cognition consistent with granulomatous meningitis, jaw claudication consistent with giant cell arteritis, tooth sensitivity to cold or gum tenderness consistent with dental abscesses, and nocturia consistent with prostatitis. Revisiting the history on several occasions may provide new clues in difficult cases.
The degree of fever, nature of the fever curve, apparent toxicity, and response to antipyretics has not been found to provide enough specificity to guide the diagnosis of FUO . Fever may be attenuated in older patients and moderated by use of steroids and nonsteroidal anti-inflammatory drugs. However, the course of the fever curve may be helpful in determining whether the disease is escalating or waning.
Initial laboratory testing in all patients — In addition to basic testing that establishes an FUO (see 'Establishing that a patient has an FUO' above), we typically perform the following minimum diagnostic evaluation for patients who have true FUO. We individualize other laboratory tests based on clinical and historical findings. (See 'Additional testing for specific circumstances' below.)
●Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) – Measurement of the ESR seems to have its greatest use in establishing a serious underlying cause of FUO. In a review of 263 patients with FUO who had ESR elevations above 100 mm/hour, 58 percent had malignancy (most commonly lymphoma, myeloma, or metastatic colon or breast cancer) and 25 percent had infection (eg, endocarditis) or systemic rheumatic diseases (eg, rheumatoid arthritis or giant cell arteritis) . However, other causes of FUO, such as drug hypersensitivity reactions, thrombophlebitis, and renal disease, particularly nephrotic syndrome, may be associated with a very high ESR in the absence of infection or malignancy. A normal ESR or CRP also suggests that a significant inflammatory process, of whatever origin, is absent; however, there are exceptions. As an example, some patients with giant cell arteritis have a normal ESR . (See "Acute phase reactants".)
●Serum lactate dehydrogenase
●Tuberculin skin test or interferon-gamma release assay (see "Use of interferon-gamma release assays for diagnosis of tuberculosis infection (tuberculosis screening) in adults")
●HIV immunoassay and HIV viral load for patients at high risk (see "Acute and early HIV infection: Clinical manifestations and diagnosis", section on 'Diagnosis')
●Three routine blood cultures drawn from different sites over a period of at least several hours without administering antibiotics, if not already performed
●Heterophile antibody test in children and young adults
●Serum protein electrophoresis
●Computed tomography (CT) scan of the chest and abdomen. Details regarding this test are found below (see 'CT for all patients' below)
Procalcitonin, a serum biomarker that is elevated with certain bacterial infections, has no clear role in distinguishing between bacterial infections and other causes of FUO, and we do not recommend checking it as part of the FUO evaluation.
Many tests are often necessary to determine the etiology for ongoing fever and the results require critical interpretation and synthesis. The diagnostic performance of any single test is limited by several factors:
●The final diagnosis is often not independent of the test being studied.
●Studies evaluating test performance are generally retrospective and rarely standardized.
●True- and false-positive rates are highly dependent on the timing of the test in relation to the course of illness and available clinical information.
●The differential diagnosis for FUO is broad, and tests do not reliably distinguish between infections, malignancy, and inflammatory conditions or identify specific conditions.
●Tests with the highest sensitivity often identify conditions that may not be the cause of fever (eg, hamartomas, thromboses).
Some experts have advocated the use of a structured protocol-based approach to testing (eg, having a minimum set of studies performed for all patients with FUO), whereas others suggest avoiding a routine battery of tests. A systematic review and meta-analysis found insufficient evidence to support one approach over the other .
Imaging studies — Most providers perform some type of imaging early during the diagnostic work-up of FUO. Various radiologic imaging studies have been studied for their ability to determine the cause of FUO. In general, studies suggest that radiographic imaging modalities are hampered by high rates of false-positive and false-negative results.
In some studies, the rates of false positives was found to be similar to that of true positives, which makes it difficult for clinicians to interpret positive results [9,28-31]. Furthermore, during an FUO work-up, a positive result on imaging often does not change management because the diagnosis would have been made even without the imaging study (ie, the test was not helpful). This was illustrated in the series cited above of 73 patients from the Netherlands seen between December 2003 and July 2005 :
●Chest radiograph – Performed in 73 patients: helpful in 6 and false positive in 8 (8 and 11 percent, respectively)
●Chest CT – Performed in 46 patients: helpful in 9 and false positive in 8 (20 and 17 percent, respectively)
●Abdominal CT – Performed in 60 patients: helpful in 12 and false positive in 17 (20 and 28 percent, respectively)
●Positron emission tomography scan – Performed in 70 patients: helpful in 23 and false positive in 10 (33 and 14 percent, respectively)
CT for all patients — We recommend an abdominal and chest CT as part of the routine evaluation of FUO. However, the rate of false-positive tests with these modalities may be similar to the rate of a true-positive result .
CT scanning of the abdomen has nearly replaced exploratory laparotomy and other radiographic tests in the search for occult abscesses or hematomas in patients with FUO. The finding of abdominal lymphadenopathy can be a clue to lymphoma or a granulomatous process. The usefulness of CT has resulted in this examination being used in nearly all patients with FUO. While magnetic resonance imaging scan can be more sensitive in certain settings (eg, the diagnosis of spinal epidural abscess), it is rarely required in the initial evaluation of FUO.
For similar reasons, CT scanning of the chest is invaluable in the identification of small nodules (indicative of fungal, mycobacterial, or nocardial infection or malignancy). The identification of hilar or mediastinal adenopathy may prompt biopsy by mediastinoscopy, providing a diagnosis of lymphoma, histoplasmosis, or sarcoidosis.
Nuclear medicine testing in selected cases — Nuclear medicine testing is more controversial than CT for the diagnosis of FUO. All nuclear medicine tests used for FUO image the whole body, but none can establish a definitive diagnosis. In many cases, these studies are used to localize a site for more specific evaluation (eg, biopsy or further imaging). In select cases, nuclear medicine findings can be suggestive enough to warrant treatment (eg, arteritis, pulmonary embolism, some tumors).
We generally reserve nuclear medicine imaging for cases in which the initial evaluation (including abdominal and chest CT) remains negative. Two types of nuclear medicine tests are used for FUO workups: labeled white blood cell (WBC) or gallium scans, and F-fluorodeoxyglucose positron emission tomography (FDG-PET).
●Labeled WBC and gallium scans – Studies comparing the value of labeled WBC or gallium scans to CT scans have had variable results. In the 1980s when CT scans and MRI were not widely available, gallium and labeled WBC scans were found to be more helpful for FUO evaluation . However, more recent studies suggest that modern CT scans are more helpful than WBC scans [29,32].
In one study of individuals with FUO in Texas from 2015 through 2019, none of 132 WBC scans identified a new unsuspected focus, and only two (1.5 percent) were classified as helpful because they led to further work-up that eventually identified an infection. Of the two helpful positive results, one detected a known fungal pneumonia but failed to detect invasive fungal sinusitis later detected by CT, and the other showed mild pelvic uptake that supported a prior MRI that was equivocal for osteomyelitis .
The nonspecific nature of these tests is of significant concern, especially for individuals with FUO in whom false-positive imaging results often lead to unnecessary invasive or costly interventions. For example, in the aforementioned study on 132 individuals with FUO in Texas, 31 (62 percent) of 50 positive WBC scans were falsely positive and 5 (10 percent) of those false-positive tests resulted in unnecessary procedures including follow-up MRIs, bronchoscopies, and biopsies (eg, bone marrow, kidney) . In another study of older adults with FUO, false-positive results occurred in 11 (23 percent) of 47 individuals who underwent gallium scans .
In most studies, the sensitivity of labeled WBC and gallium scans for identifying focal causes of FUO is high, and negative predictive values range from 75 to 90 percent [29-31,33]. However, recent studies have suggested that the negative predictive value for these scans is high because the scans are typically ordered at a point in the work-up when a source for fever is unlikely to be found. For example, in one study, the negative predictive value for WBC scans in 132 patients with FUO was 89 percent, compared with a negative predictive value of 88 percent for a conventional work-up had the WBC never been ordered .
●F-fluorodeoxyglucose positron emission tomography – FDG-PET appears to be more sensitive than WBC scans in identifying anatomic sites of inflammation, infection, and malignancy. This modality may find a valuable place in the evaluation of FUO, but additional data are needed to determine its added value beyond repeated clinical evaluation over time and routine CT [34-37]. As noted above, a positive result on FDG-PET may be as likely to be a false positive as it is to be a true positive .
Additional testing for specific circumstances — When the history, examination, or imaging suggests a possible source, specific testing should be performed. Examples include:
●Subtle central nervous system symptoms or signs should prompt a lumbar puncture and imaging of the head and/or spine.
●In the United States, a travel history to the Midwest or the deserts of the West should raise the question of a fungal process like histoplasmosis or coccidioidomycosis, respectively. Testing for the suspected fungal pathogen in individuals who have resided in an endemic area can be useful. (See "Diagnosis and treatment of pulmonary histoplasmosis" and "Diagnosis and treatment of disseminated histoplasmosis in HIV-uninfected patients" and "Coccidioidomycosis: Laboratory diagnosis and screening".)
●Individuals who have recently visited or resided in a malaria-endemic region should have blood sent for a thick and thin smear. (See "Laboratory tools for diagnosis of malaria".)
●Other appropriate tests for returning travelers are discussed separately. (See "Evaluation of fever in the returning traveler".)
●A history of trauma, adjacent infection or intravenous drug use may suggest thrombophlebitis of the legs, arms, or pelvic vessels. Venous duplex imaging can be diagnostic. Fever usually responds to anticoagulation within several days.
●Molecular tests include next-generation sequencing, broad-range or multiplex polymerase chain reaction (PCR) assays, D1-D2 region assays, and others. We suggest reserving these types of tests for patients in whom FUO is persistent and diagnosis is elusive despite thorough work-up.
There are no studies evaluating these tests' operating characteristics in clinical use, early versus later use in FUO, ability to differentiate colonization from infection, or sensitivity when performed after antimicrobial therapy.
In several case reports, molecular diagnostic assays have detected infectious etiologies in individuals with FUO for whom cultures and other workup yielded no diagnosis [37,38]. The use of these methodologies has led to such diagnoses as culture-negative tuberculosis, bacteremia due to probiotic supplements, non-tuberculous mycobacterial splenic infection, and Abiotrophia endocarditis.
Biopsy — Biopsy is a critical modality in the directed (as opposed to screening) evaluation of FUO.
We suggest performing a biopsy when the clinical data support a diagnosis that can be confirmed from a tissue sample, especially when the risks are low (e.g., skin biopsy). Blind biopsies rarely yield helpful results.
However, like all diagnostic tests, biopsies can have false-negative or false-positive results. For example, false-negatives can occur due to inadvertently sampling an unaffected site, and false-positives can occur when a concurrent condition is detected that is not causing the FUO.
The following examples include data from the Netherlands study of 73 patients cited above on the utility of biopsy of different sites :
●Liver biopsy for possible miliary tuberculosis, granulomatous hepatitis, or other granulomatous diseases such as sarcoidosis – Liver biopsy was performed in 7 patients; it was helpful in 1 and false positive in 3.
●Lymph node biopsy for possible malignancy, especially lymphoma, or infections such as cat-scratch disease – Lymph node biopsy was performed in 11 patients; it was helpful in 5 and false positive in 3.
●Temporal artery to look for giant cell arteritis or biopsy of an affected tissue to diagnose a vasculitic process such as polyarteritis nodosa – Temporal artery biopsy was performed in 14 patients; it was helpful in 1 with no false positives.
●Pleural or pericardial biopsy in the evaluation of extrapulmonary tuberculosis.
●Bone marrow biopsy was performed in 19 patients; it was helpful in 2 and false positive in 1.
Two retrospective reviews of bone marrow biopsies to evaluate FUOs demonstrated high diagnostic yields and high prevalence of hematologic malignancies [39,40]. The authors did not define the prevalence of infectious diseases at the hospitals under study nor did they define the decision-making that led physicians to request bone marrow biopsies. However, the observations in both studies were similar: lymphomas constituted >40 percent of diagnoses, whereas infections were detected in <15 percent of patients. Other causes of FUO included acute myeloid leukemia, myelodysplastic syndromes, sarcoidosis, systemic mastocytosis, and disseminated granulomatosis. In both studies, hematologic malignancies were strongly predicted by the presence of leukoerythroblastic changes in peripheral blood and a greatly elevated ferritin level (>1000 ng/mL); in one of the studies, hematologic malignancies were also predicted by the presence of splenomegaly .
ROLE OF THERAPEUTIC TRIALS — Therapeutic trials of antimicrobials or glucocorticoids, while tempting in the effort to "do something," rarely establish a diagnosis. In addition, the diagnostic yield of blood cultures and cultures of biopsy material will be reduced following the initiation of antibiotics. Antimicrobial agents could be expected to suppress, but not cure, many infectious processes such as an occult abscess since adjunctive drainage would usually be required.
Antibiotics can have effects on other infections than the ones to which therapy is directed. Rifampin, for example, used in a therapeutic trial for tuberculosis may suppress staphylococcal osteomyelitis or diminish the ability to detect difficult-to-isolate organisms causing endocarditis. The appropriate duration of a therapeutic trial is also unclear since a number of infections such as endocarditis or pelvic inflammatory disease can take as much as one week for fever to abate, even with appropriate therapy. Empiric antibiotics should never be started solely to treat fever.
A therapeutic trial of glucocorticoids for an inflammatory process should not replace relevant biopsies for steroid-responsive diseases such as sarcoidosis, other granulomatous diseases, or vasculitis. A careful evaluation for infection should precede such a trial.
Urgent FUO therapy — When morbid illnesses like endocarditis, temporal arteritis, central nervous system tuberculosis, and leptospirosis present as FUOs, they rarely progress rapidly enough to warrant urgent treatment. However, when illnesses like these are suspected, we speed diagnostic testing and treat empirically.
Antipyretics improve patients' comfort, reducing headache, myalgias, arthralgias, and fatigue. However, drugs with antipyretic effects may delay or obscure early symptoms and signs of specific diseases. Thus, we try to avoid prescribing acetaminophen, nonsteroidal anti-inflammatory drugs, or glucocorticoids.
The use of antipyretics is discussed in greater detail separately. (See "Pathophysiology and treatment of fever in adults", section on 'Treatment of fever and hyperpyrexia'.)
OUTCOME — The outcome of patients with an FUO depends upon the underlying diagnosis and any comorbid conditions. The rate of no diagnosis in studies of FUO published since 1990 has varied from 9 to 51 percent [4-9,29].
Among children with FUO, 88 percent of those caused by infections have no sequelae.
Most adults who remain undiagnosed after an extensive evaluation have a good prognosis [7,8,41]. This was illustrated in a study of 199 patients with FUO, 61 of whom (30 percent) were discharged from the hospital without a diagnosis :
●A definite diagnosis was established in 12 (20 percent), usually within two months after discharge.
●Thirty-one (51 percent) became symptom-free during hospitalization or shortly following discharge.
●Eighteen (30 percent) had persisting or recurring fever for several months or even years after discharge, 10 of whom were considered to be finally cured.
●Four were treated with glucocorticoids and six required intermittent therapy with nonsteroidal anti-inflammatory drugs.
●Six died, but the cause of death was considered to be related to the disease that caused FUO in only two cases.
Similar findings were noted in the Netherlands series of 73 patients cited above . Among the 37 patients with no diagnosis who were followed for at least six months, 16 spontaneously recovered, 5 recovered with nonsteroidal anti-inflammatory drugs or glucocorticoids, 15 had persistent fever, and 1 died.
SUMMARY AND RECOMMENDATIONS
●Definition – Fever of unknown origin (FUO) is defined as fever higher than 38.3ºC on several occasions lasting for at least three (some use two) weeks without an established etiology despite intensive evaluation and diagnostic testing. (See 'Definition' above.)
●Etiology – Three general categories account for the majority of FUO cases: infections, malignancies, and systemic rheumatic diseases. (See 'Etiology' above.)
●Factors that affect etiology – The likelihood of a specific etiology varies substantially based on a patient's age, exposures, and immune status. (See 'Epidemiology' above.)
●Work-up – The most important aspects of the evaluation of a patient with FUO are to take a meticulous history, perform a detailed physical examination, and reassess the patient frequently. (See 'History and physical examination' above.)
•Diagnostic tests – We suggest the following minimum diagnostic evaluation: blood cultures, erythrocyte sedimentation rate or C-reactive protein, serum lactate dehydrogenase, HIV antibody test and viral load, rheumatoid factor, heterophile antibody test for mononucleosis, creatine phosphokinase, antinuclear antibodies, tuberculin skin test or interferon-gamma release assay, serum protein electrophoresis, and computed tomography scan of abdomen and chest. (See 'Initial laboratory testing in all patients' above and 'Additional testing for specific circumstances' above and 'CT for all patients' above.)
•Role of biopsy – We suggest performing a biopsy when the clinical data support a diagnosis that can be confirmed from a tissue sample, especially when the risks are low (eg, skin biopsy). (See 'Biopsy' above.)
●Outcome – The diagnostic evaluation may fail to identify an etiology in as many as 30 to 50 percent of patients. Most adults who remain undiagnosed have a good prognosis. (See 'Outcome' above.)
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