Continuing Education Activity
Fever of unknown origin (FUO) was first described by Dr. Petersdorf and Dr. Beesom in 1961. FUO was defined as a temperature of 101 F (38.3 C) or higher with a minimum duration of 3 weeks without an established diagnosis after an intensive 1-week investigation in the hospital. Today, due to technological advances allowing for sophisticated outpatient evaluations, the 1-week inpatient investigation is no longer required. This activity reviews the cause and presentation of fever of unknown origin and highlights the role of the interprofessional team in its management.
- Describe the workup of a patient with fever of unknown origin.
- Outline the causes for fever of unknown origin.
- Summarize the treatment of patients with fever of unknown origin.
- Review the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by fever of unknown origin.
Fever of unknown origin (FUO) was first described by Dr. Petersdorf and Dr. Beesom in 1961. FUO was defined as a temperature of 101F (38.3 C) or higher with a minimum duration of 3 weeks without an established diagnosis despite at least 1 week's investigation in the hospital. This definition was later changed to accommodate technological advances allowing for sophisticated outpatient evaluations, increasing numbers of immunocompromised individuals including those with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), and more complex treatment options becoming available. The revised definition proposed by Durack and Street in 1991 divided cases into four distinct subclasses: classic FUO, nosocomial FUO, neutropenic FUO, and HIV-related FUO. 
A comprehensive history and physical examination can aid in diagnosis and direct diagnostic testing. Recommended investigations for work-up include complete blood count (CBC) with differential, 3 sets of blood cultures (from different sites, several hours apart, and before initiation of antibiotic therapy, if indicated), chest radiograph, complete metabolic panel (including hepatitis serologies if LFTs are abnormal), urinalysis with microscopy and urine culture, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibodies (ANA), rheumatoid factor (RA), cytomegalovirus IgM antibodies or virus detection in blood, heterophile antibody test, tuberculin skin test, HIV testing and computed tomography (CT) scan of the abdomen.
Over 200 malignant/neoplastic, infectious, rheumatic/inflammatory, and miscellaneous disorders can cause FUO. Clinicians often order non-clue-based imaging and specific testing early in the FUO workup, which may be misleading and is certainly not economical. Despite extensive workup and diagnostic advances, up to 51% of FUO cases remain undiagnosed. In modern medicine, FUO remains one of the most challenging diagnoses.
It is important to note that immunocompromised and HIV patients may require an entirely different approach in diagnosing and treatment of recurrent fevers. This article focuses on FUO in immunocompetent adult patients.
Etiologic categories of FUO include infections, neoplasms, connective tissue disease and miscellaneous. Common causes of fever in the different subclasses are discussed below:
- Classic FUO: The frequency of each category varies by both time and location, although, endocarditis, complicated urinary tract infections, abscesses, and tuberculosis (TB) are consistently reported in patients with classic FUO. In patients over the age of 65, connective tissue diseases are determined to be the cause of fever more frequently. Fever in travelers is more likely to be secondary to infections such as malaria, typhoid fever, and acute HIV.
- Nosocomial FUO: Healthcare-associated fevers can be due to drug fever, complications post-operatively, venous thromboembolic disease, malignancy, transfusion-related reactions, or Clostridium difficile infection. Risk factors such as surgical procedures, instrumentation, intravascular devices, immobilization, and medications can help determine diagnostic testing necessary to obtain a diagnosis.
- Neutropenic FUO: Fevers are common in this subclass and are frequently due to infection.
- HIV-related FUO: Fevers can be present during acute illness, but are also common in the setting of untreated infection signifying additional infection with opportunistic organisms.
Epidemiology of FUO varies based on etiology of fever, age group, geography, environmental exposure, and immune/HIV status. In developing countries, an infectious etiology of FUO is most prevalent whereas, in developed countries, FUO is likely due to non-infectious inflammatory disease.
History and Physical
There is no clear-cut diagnostic approach to FUO. Thorough history with a focus on most probable etiology based on patient’s symptoms is the key to pinpoint the origin of FUO. Information about previous illnesses, localizing symptoms, alcohol intake, home medications, occupational exposures, pets, travel, and familial disorders should not be overlooked. Constellation of patient-reported symptoms should help clinicians narrow down the etiology of the etiologic category of fevers as each of these has clinical hallmarks. For example, if a patient presents with B-symptoms, early satiety, and significant weight loss, a clinician should pursue a malignancy workup. On the other hand, if a patient presents with rigors, an infectious etiology should be considered, while joint involvement is a hallmark of rheumatologic disorders.
Importantly, fevers should be verified in a clinical setting, and fever patterns should be analyzed. Fever pattern analysis can provide additional clues to specific infectious culprits, such as malaria which can cause tertian and quartan fever patterns.
If an infectious etiology is likely, history of presenting illness should include prior invasive procedures/surgeries, dentition, TB exposure, pet contacts, mosquito/tick bites, rodent exposure, history of blood transfusions, and immunosuppressive drugs. Important physical exam findings include a new heart murmur which could be suggestive of bacterial endocarditis, spinal tenderness indicating vertebral osteomyelitis, splenomegaly concerning for miliary TB, epstein-barr virus (EBV), and cytomegalovirus (CMV) and epididymal nodule concerning for extrapulmonary TB.
Similarly, when considering malignancy, it is important to inquire about unintentional weight loss, age-appropriate cancer screening, family history of cancer, smoking, and alcohol use. On physical exam, one could notice relative bradycardia suggestive of lymphoma/ central nervous system (CNS) malignancy, a new heart murmur pointing toward atrial myxoma, or sternal tenderness which could be concerning for a myeloproliferative disorder. Isolated hepatomegaly and FUO could be indicative of a hepatoma or liver metastases.
When considering rheumatologic disorder and FUO, ask about muscle and joint pain/stiffness, oral ulcers, and family history of autoimmune conditions. Rheumatologic etiology of FUO is less likely if a patient reports symptoms of rigors or chills. Fever distribution analysis could differentiate periarteritis nodosa (morning fevers) vs. adult Still’s disease (double quotidian). On physical exam, it is important to look for oral ulcers (Behcet disease, systemic lupus erythematosus [SLE]), unequal pulses (Takayasu arteritis), lymphadenopathy (SLE, RA, sarcoidosis), and rashes (sarcoidosis, SLE, adult Still disease). An epididymal nodule is a clue for periarteritis nodosa, SLE, and sarcoidosis whereas hepatomegaly without splenomegaly argues against rheumatologic disorders.
Cirrhosis and Crohn’s disease are often overlooked as miscellaneous causes of FUO. If suspected, it is important to inquire about past medical history, history of alcohol intake, intravenous drug use, non-alcoholic hepatosteatosis (NASH), and hepatitis. On physical examination, splenomegaly is an important diagnostic clue for Crohn’s disease and liver cirrhosis.
When working up the differential diagnosis for FUO, it is important to remember that the cause is more likely a subtle or atypical manifestation of a common disease rather than a rare disease. Diagnosing a cause of FUO can be a cumbersome task and requires repeated diligent and thorough history taking along with a complete physical examination. Initial diagnostic testing should include:
- Complete blood count with differential
- Complete metabolic panel
- Urine analysis with microscopy and urine culture
- Three sets of blood cultures (from different sites, several hours apart, and prior to initiation of antibiotic therapy)
- Chest radiograph
- Lactate dehydrogenase (LDH)
- Creatinine phosphokinase
- Cytomegalovirus IgM/PCR
- Heterophile antibody test
- Tuberculin skin test or interferon-gamma release assay
- HIV immunoassay
- CT scan of abdomen
- CT scan of chest
To diagnose FUO, non-invasive testing outlined above should have been inconclusive. At this point, a clinician should exclude surreptitious manipulation of the thermometer and analyze patients' medication lists to evaluate for drug-induced fevers.
In the past, nuclear medicine testing was generally reserved for cases that remain undiagnosed after thorough initial evaluation. Recent European studies suggest utilizing fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan earlier in FUO workup, if available. FDG-PET/CT and FDG/PET are highly sensitive and non-invasive diagnostic techniques for anatomic localization of infectious, inflammatory, or neoplastic processes and, although nonspecific, can guide further definitive tests such as biopsy or aspiration.
If FDG-PET is not available, labeled leukocyte studies could be used as an alternative; however, they might have a lower diagnostic yield. Gallium- and indium-labeled leukocyte studies are highly sensitive but not specific enough for establishing a diagnosis. However, these tests are helpful to localize the involved site for a targeted evaluation with a CT scan. Note that indium scans have a high rate of false negatives with bone infections. Positron emission tomography can aid in detecting obscure infections or malignancies.
Cardiac echocardiography can be helpful if culture-negative endocarditis or atrial myxoma is suspected.
The most common invasive tests associated with FUO are biopsies of lymph nodes, liver, bone marrow, epididymal nodule, and temporal artery. These tests are performed only if the clinical picture or initial tests reveal findings that require histopathological evaluation. Biopsies are most commonly used to diagnose malignancy, certain infections, myeloproliferative disorders, and inflammatory conditions causing FUO. For example, temporal artery biopsy should be considered in a patient older than 60 years old and with significantly elevated ESR, particularly, if there are other symptoms suggestive of giant cell arteritis. Additionally, if the physical examination reveals lymphadenopathy in a patient with FUO, lymph node biopsy is recommended and may reveal definitive etiology of fevers.
Treatment / Management
There is no single standard FUO management protocol given the variety of possible etiologies. The most important thing is to investigate and/or rule out all possible diagnoses. Please note that empiric antibiotics are not indicated unless the patient with FUO is neutropenic. Antibiotics may delay the diagnosis of some occult infections. Empiric glucocorticoids are also not indicated unless there is strong clinical suspicion for specific rheumatologic diagnosis. However, in patients whose condition is deteriorating empiric therapeutic trials of antibiotics, steroids, or antituberculous agents may be considered.
The naprosyn test can be performed to differentiate infectious and neoplastic etiologies of FUO. The test is conducted over 3 to 4 days, during which patient temperatures are trended while a patient is given naproxen. If temperatures decrease substantially, malignant/neoplastic etiology is likely. However, if temperatures remain the same or only minimally decrease, the FUO is likely of infectious origin. The utility of naproxen test is not well studied, and at this time, experts believe the test is not specific enough to be useful for the individual patient.
It is important to remember that up to 51% of cases remain undiagnosed. However, the prognosis for these patients is generally good, and it is highly probable that FUO will spontaneously resolve in weeks to months. In stable patients without a diagnosis, non-steroidal anti-inflammatory drugs could be used for symptomatic management.
The differential diagnosis for FUO is broad but can be grouped into 4 following categories based on etiology: infections, neoplasms, connective tissue disease, and miscellaneous.
Infection accounts for about a third of cases of FUO. The most common infections causing FUO are miliary tuberculosis (TB), brucellosis, and Q fever, followed by intraabdominal, pelvic, intranephric and perinephric abscesses, typhoid/enteric fevers, toxoplasmosis, cat scratch disease (CSD), HIV, CMV, EBV, and extrapulmonary (renal, central nervous system [CNS]) TB. Note that in HIV population 75% causes of FUO are infectious but rarely due to HIV itself.
Another third of FUO cases is due to rheumatologic and inflammatory disorders, such as adult Still's disease, giant cell/temporal arteritis, periarteritis nodosa, microscopic polyangiitis, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). It could be rarely associated with Takayasu's arteritis, Kikuchi disease, sarcoidosis, Felty syndrome, Gaucher disease, polyarticular gout, pseudogout, antiphospholipid syndrome (APS), Behcet's disease, and Marshall syndrome.
Neoplasms and malignancies account for up to 18% of FUO etiologies. The most common neoplasms associated with FUO are lymphoma and renal cell carcinoma, followed by acute myeloid leukemia and myeloproliferative disorders. FUO is rarely associated with atrial myxoma, multiple myeloma, colon carcinoma, pancreatic carcinoma, hepatoma, CNC metastasis, liver metastasis, and systemic mastocytosis.
The remainder of FUO etiologies is classified as miscellaneous. These include drug-induced fevers, liver cirrhosis, subacute thyroiditis, and Crohn’s disease. Less commonly FUO is caused by deep vein thrombosis, pulmonary embolus, hematomas, familial Mediterranean fever, hypothalamic dysfunction, hypertriglyceridemia (type V), and fictitious fever.
Prognosis of FUO varies based on the etiologic agent of one's symptoms, however poorer prognosis has been reported in elderly patients and those diagnosed with a malignancy.
Complications also vary based on the diagnosis of certain diseases that may have been causing FUO. Interestingly, patients with an undiagnosed cause of FUO have favorable outcomes and no reported complications after fever resolution. 
Deterrence and Patient Education
It is important for patients to note the difficulties associated with the diagnostic process when one presents with fever of unknown origin. Patients should work together with physicians by providing a thorough history to aid in directed diagnostic testing.
Enhancing Healthcare Team Outcomes
In modern medicine, FUO remains one of the most challenging diagnoses as it can be caused by over 200 neoplastic, infectious, inflammatory, and miscellaneous disorders. Diagnosing FUO requires a thorough history, repeated physical examinations, and selective diagnostic testing. Clinicians should avoid taking a “shot-gun” approach early in the FUO workup as it can be misleading. Directed diagnostic testing based on a patient's history and physical is more likely to yield a diagnosis and is more cost-effective.
An interdisciplinary approach is important while pursuing work-up for FUO. It is important to communicate the importance of monitoring fevers without treatment when appropriate with nursing staff to evaluate fever curves and guide additional testing. Primary care physicians and hospitalists should work together with specialists (based on etiology, but could include Infectious Diseases, Rheumatology, or Hematology/Oncology) to ensure early diagnosis and treatment. Discussing the case with pharmacy can also be beneficial in determining whether any medications the patient is taking can be causing drug-induced fevers.