Fever of Unknown Origin

Etiology

The causes of fever of unknown origin (FUO) are often common conditions presenting atypically. The list of causes is extensive, and it is broken down into broader categories, such as infection, noninfectious inflammatory conditions, malignancies, and miscellaneous.

Noninfectious Inflammatory Causes of FUO

• Giant cell (temporal) arteritis
• Adult Still disease (juvenile rheumatoid arthritis)
• Systemic lupus erythematosus (SLE)
• Periarteritis nodosa/microscopic polyangiitis (PAN/MPA)
• Rheumatoid arthritis (RA)
• 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

• Tuberculosis (TB)
• Q fever
• Brucellosis
• HIV infection
• Abdominopelvic abscesses
• Cat scratch disease (CSD)
• Epstein-Barr virus (EBV) infection
• Cytomegalovirus (CMV) infection
• Enteric (typhoid) fever
• Toxoplasmosis
• Extrapulmonary TB
• Organ-based infectious causes of FUO:
  • Subacute bacterial endocarditis (SBE)
  • Chronic sinusitis/mastoiditis
  • Chronic prostatitis
  • Discitis
  • Vascular graft infections
  • Whipple disease
  • Multicentric Castleman disease (MCD)
  • Cholecystitis
  • Lymphogranuloma venereum (LGV)
• Tickborne infections:
  • Babesiosis, Ehrlichiosis
  • Anaplasmosis
  • Tickborne relapsing fever (rodent-infested cabins)
• Regional infections:
  • Histoplasmosis
  • Coccidioidomycosis
  • Leptospirosis
  • Visceral leishmaniasis
  • Rat-bite fever
  • Louse-borne relapsing fever

Malignant and Neoplastic Causes of FUO

• Lymphoma
• Renal cell carcinoma
• Myeloproliferative disorder
• Acute myelogenous leukemia
• Multiple myeloma
• Breast/liver/pancreatic/colon cancer
• Atrial myxoma
• Metastases to brain/liver
• Malignant histiocytosis

Miscellaneous Causes of FUO

• Cirrhosis (due to portal endotoxins)
• Drug fever
• Thyroiditis
• Crohn disease
• Pulmonary emboli
• Hypothalamic syndrome
• Familial periodic fever syndromes
• Cyclic neutropenia
• Factitious fever

Common Causes of Fever in the Different Subclasses

• 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.[7] Fever in travelers is more likely to be secondary to infections such as malaria, typhoid fever, and acute HIV.[8]
• 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.[7] Risk factors such as surgical procedures, instrumentation, intravascular devices, immobilization, and medications can help determine the 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.[9]

Epidemiology

Epidemiology of fever of unknown origin (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.[6]

History and Physical

There is no clear-cut diagnostic approach to fever of unknown origin (FUO). Thorough history with a focus on the most probable etiology based on the 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 providers 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, the provider 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.[4]

Important Aspects of History

• Family history
• Immunization history
• Dental history
• Occupational history
• Travel history
• Nutrition and weight history
• Drug history (over-the-counter medications, illicit substances)
• Sexual history
• Recreational habits
• Animal contacts
• Surgery, trauma, or procedures

Fever Patterns

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.

• Tertian or quartan fever in prolonged malaria (occurring every third or fourth day)
• Undulant fever in brucellosis (fevers and sweats in the evening, resolving by morning)
• Tick-borne relapsing fever in borreliosis (week-long fevers with week-long remissions)
• Pel-Ebstein 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, malaria, and typhoid

Historical Clues and Physical Examination in Infectious Causes of FUO

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.

• In case of an intraabdominal abscess, perinephric abscess, psoas abscess there would be a previous history of abdominal surgery, trauma, or a history of peritonitis, endoscopy, urologic or gynecologic procedures.
• A history of exposure to unpasteurized dairy may suggest brucellosis, Q fever, Yersinia enterocolitica.
• Exposure to birds may suggest Chlamydia psittaci infection.
• Exposure to cats may suggest toxoplasmosis or cat scratch disease.
• Consider HIV, disseminated gonorrhea in travelers, and sexual encounters without barrier precautions.
• Acute Epstein-Barr virus (EBV) infection in day care centers as it spreads easily.

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.[4]

Historical Clues and Physical Examination in Malignant Causes of FUO

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.[4]

Historical Clues and Physical Examination in non Infectious Causes of FUO

Collagen vascular and autoimmune diseases can manifest as FUO if the fever precedes other, more specific manifestations such as arthritis, pneumonitis, or renal involvement. 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 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.[4]

Historical Clues and Physical Examination in Miscellaneous Causes of FUO

Cirrhosis and Crohn 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 disease and liver cirrhosis.[4]

Evaluation

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.

Non-invasive Tests

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
• Erythrocyte sedimentation rate (ESR)
• C-reactive protein (CRP)
• Lactate dehydrogenase (LDH)
• Creatinine phosphokinase
• ANA
• Rheumatoid factor
• Cytomegalovirus IgM/PCR
• Heterophile antibody test
• Tuberculin skin test or interferon-gamma release assay
• HIV immunoassay
• CT scan of the abdomen
• CT scan of the chest
• Cardiac echocardiography can be helpful if culture-negative endocarditis or atrial myxoma is suspected.

To diagnose FUO, the 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.[6]

Nuclear Medicine Tests

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.[10][11][12] 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.

Invasive Tests

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 fever.

Endoscopic examination of the upper and lower gastrointestinal tract should be done, including retrograde cholangiography when indicated as for Crohn disease, biliary tract disease, and gastrointestinal tumors. Crohn disease is the most common gastrointestinal cause of FUO. Diarrhea and other abdominal symptoms are sometimes absent in young adults.

Treatment / Management

There is no single standard FUO management protocol given the variety of possible etiologies. The most important thing is to investigate and rule out all possible diagnoses. Specific treatment should be started, once a diagnosis is made. 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 a specific rheumatologic diagnosis. However, in patients whose condition is deteriorating empiric therapeutic trials of antibiotics, steroids, or antituberculous agents may be considered.[5] Other exceptions to start antibiotic or steroid treatment despite inconclusive are:(B2)

• Culture-negative endocarditis
• Cryptic disseminated TB (or, occasionally, other granulomatous infections)
• Temporal arteritis with suspected vision loss

Patients with FUO rarely need surgical treatment.

Specific Examples of Treatment

• In patients with hepatic granulomas, 50% respond to corticosteroid treatment while the other 50% resolve spontaneously.
• Patients with giant cell arteritis are treated with high doses of steroids, and if the patient is very ill or has a significant ocular compromise, intravenous steroids should be administered.
• In polymyalgia rheumatica, the treatment is steroid therapy.
• When drug fever is suspected, discontinue the implicated drug. The patient would be afebrile after two days of stopping the causative drug.

The naproxen 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 the 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.[6]

Differential Diagnosis

The differential diagnosis for FUO is broad but can be grouped into the following four 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
• Q fever
• Intraabdominal, pelvic, intranephric, and perinephric abscesses
• Typhoid/enteric fever
• Actinomycosis
• Amebiasis
• Atypical mycobacterial infection
• Blastomycosis
• Brain abscess
• Campylobacter infections
• Cholangitis
• Cholelithiasis
• Chagas disease
• Candidiasis
• Dengue fever
• Diabetic ulcers
• Empyema thoracis
• Empyema gallbladder
• Toxoplasmosis
• Giardiasis
• Hepatitis A-E
• Liver abscess
• Lung abscess
• Leptospirosis
• Leishmaniasis
• Libman-sacks endocarditis
• Cat scratch disease (CSD)
• Malaria
• Mycoplasma
• Mucormycosis
• SARS COVID 19
• Pelvic inflammatory disease
• HIV
• Cytomegalovirus
• Epstein-Barr virus
• Extrapulmonary (renal, central nervous system) TB

Note that in the HIV population 75% of cases of FUO are infectious but rarely due to HIV itself.[4]

Another third of FUO cases is due to rheumatologic and inflammatory disorders, such as:

• Adult Still disease
• Giant cell/temporal arteritis
• Periarteritis nodosa
• Microscopic polyangiitis
• Rheumatoid arthritis (RA)
• Systemic lupus erythematosus (SLE)
• Takayasu arteritis
• Kikuchi disease
• Sarcoidosis
• Felty syndrome
• Gaucher disease
• Polyarticular gout
• Pseudogout
• Antiphospholipid syndrome (APS)
• Behcet disease
• Marshall syndrome[4]

Neoplasms and malignancies account for up to 18% of FUO etiologies. The most common neoplasms associated with FUO are:

• Lymphoma
• Renal cell carcinoma
• Acute myeloid leukemia
• Myeloproliferative disorders
• Atrial myxoma
• Multiple myeloma
• Colon carcinoma
• Pancreatic carcinoma
• Hepatoma
• CNC metastasis
• Liver metastasis
• Systemic mastocytosis[4]

The remainder of FUO etiologies is classified as miscellaneous. These include:

• Drug-induced fevers
• Liver cirrhosis
• Subacute thyroiditis
• Crohn disease
• Deep vein thrombosis
• Pulmonary embolus
• Hematomas
• Familial Mediterranean fever
• Hypothalamic dysfunction
• Hypertriglyceridemia (type V)
• Fictitious fever[4]

Prognosis

The prognosis of fever of unknown origin (FUO) varies based on the etiology of the fever and by the nature of the underlying disease. However poorer prognosis has been reported in elderly patients and those diagnosed with a malignancy. Children without a discernible cause, eventually, do better than adults. 

Complications

Complications also vary based on the diagnosis of certain diseases that may have been causing fever of unknown origin (FUO). Interestingly, patients with an undiagnosed cause of FUO have favorable outcomes and no reported complications after fever resolution.[13]