Approach to Fever of Unknown Origin
Definition& Classification:1,2
Definitions: Common Etiologies:
A. Classic FUO: Infection (especially TB, endocarditis,
(1) Daily or intermittent fever > 38.3 °C osteomyelitis, intra-abdominal abscess),
malignancy (especially lymphoma, renal
(2) Duration of at least 3 consecutive weeks cell carcinoma, hepatocellular), collagen
(3) No source identified by clinical evaluation vascular disease
despite: a.) 3 days of hospital evaluation
OR
b.) 3 outpatient visits
B. Nosocomial FUO: Clostridium difficile colitis, drug-induced
(1) Daily or intermittent fever > 38.3 °C fever, alcohol/drug withdrawal,
pulmonary embolism, septic
(2) Hospitalized ≥ 24 hours with no fever on thrombophlebitis, sinusitis, acalculus
admission cholecystitis, pancreatitis
(3) Fever evaluation of at least 3 days
C. Immune-deficient FUO: Opportunistic bacterial infections,
(1) Daily or intermittent fever > 38.3 °C aspergillosis, candidiasis, herpes virus
(2) ANC < 500/mm3
(3) No diagnosis after 3 days of appropriate in-hospital
investigation
D. HIV-associated FUO: Cytomegalovirus, Mycobacterium avium-
(1) Daily or intermittent fever > 38.3 °C intracellulare complex, Pneumocystis
jiroveckii pneumonia, drug-induced,
(2) confirmed HIV infection
Kaposi's sarcoma, lymphoma
(3) fever duration > 3 weeks for outpatients and > 3
days for inpatients
Etiology2,3
1) Infectious Causes of FUO :
Tuberculosis (TB) Organ-based infectious causes Tickborne infections: Regional infections:
of FUO: o Babesiosis,
Abdomino-pelvic o Histoplasmosis
o Subacute bacterial
abscesses Ehrlichiosis
endocarditis (SBE) o Coccidioidomycosis
Brucellosis o Anaplasmosis
o Chronic sinusitis/mastoiditis o Leptospirosis
HIV infection o Tickborne relapsing
Hepatitis A-E o Visceral
Epstein-Barr virus o Chronic prostatitis fever (rodent- leishmaniasis
(EBV) infection o Discitis infested cabins) o Rat-bite fever
Cytomegalovirus Vascular graft infections
o o Louse-borne
(CMV)
o Whipple disease relapsing fever
Cat scratch disease
(CSD) o Multicentric Castleman
Enteric (typhoid) disease (MCD)
fever
o Cholangitis,Cholecystitis,Em
Toxoplasmosis
pyema gallbladder
SARS COVID 19
Malaria o Lymphogranuloma venereum
Q fever (LGV)
2) Malignant Causes of FUO 3) Inflammatory Causes of FUO 4) Miscellaneous Causes of FUO
Lymphoma Giant cell (temporal) arteritis Complications from cirrhosis
Renal cell carcinoma Adult Still disease (juvenile
Hepatitis (alcoholic,
Myeloproliferative disorder rheumatoid arthritis) granulomatous, or lupoid)
Acute myelogenous Systemic lupus
Drug fever
leukemia erythematosus (SLE)
Multiple myeloma Periarteritis
Thyroiditis
Breast/liver/pancreatic/colon nodosa/microscopic Crohn disease
cancer polyangiitis (PAN/MPA) Pulmonary emboli
Atrial myxoma Rheumatoid arthritis (RA) Hypothalamic syndrome
Metastases to brain/liver Antiphospholipid syndrome Familial periodic fever
Malignant histiocytosis (APS) syndromes
Gout
Cyclic neutropenia
Pseudogout
Factitious fever
Behçet disease
Sarcoidosis
Felty syndrome
Takayasu arteritis
Kikuchi disease
Periodic fever adenitis
pharyngitis aphthous ulcer
(PFAPA) syndrome
Agents Commonly Associated with Drug-Induced Fever
o Allopurinol o Isoniazid
o Captopril o Meperidine
o Cimetidine o Methyldopa
o Clofibrate o Nifedipine
o Erythromycin o Nitrofurantoin
o Heparin o Penicillin
o Hydralazine o Phenytoin
o Hydrochlorothiazide o Procainamide
o Quinidine
Diagnostic approach1,2
Step1: History and Physical Examination:
I. Important Aspects of History
Family history
Immunization 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
II. Fever Patterns
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, miliary
TB, or visceral leishmaniasis
Morning temperature spikes seen in miliary TB, typhoid/enteric fever, Whipple’s disease
Faget sign (relative bradycardia with fever) seen in typhoid, malaria, babesiosis, ehrlichiosis, yellow
fever, Q fever
III. Careful assessment for lesions on the skin, lesions in the oropharynx, teeth (dental abscesses),
visceromegalies, lymph node enlargement, pelvic and abdominal masses or heart murmurs.
IV. Fundoscopy must be performed whenever possible.
If an infectious etiology is likely,
Ask about: Prior invasive procedures/surgeries, dentition, TB exposure, pet contacts, mosquito/tick bites,
rodent exposure, history of blood transfusions, and immunosuppressive drugs.
History & Physical Exam Finding Clinical Correlate
A. History clues
A previous history of abdominal surgery, trauma, Intraabdominal abscess, perinephric abscess, psoas
or a history of peritonitis, endoscopy, urologic or abscess
gynecologic procedures.
A history of exposure to unpasteurized dairy May suggest brucellosis, Q fever, Yersinia
enterocolitica.
Exposure to birds Chlamydia psittaci infection.
Travelers and sexual encounters without barrier Consider HIV, disseminated gonorrhea
precautions.
B. Physical Exam
A new heart murmur Bacterial endocarditis
Spinal tenderness Vertebral osteomyelitis
Splenomegaly Miliary TB, epstein-barr virus (EBV), and
cytomegalovirus (CMV)
If malignant etiology is likely,
Ask about: Unintentional weight loss, age-appropriate cancer screening, family history of cancer, smoking, and
alcohol use.
Physical Exam Finding Clinical Correlate
Relative bradycardia Lymphoma, central nervous system (CNS) malignancy
New heart murmur Atrial myxoma
Sternal tenderness Myeloproliferative disorder
Isolated hepatomegaly Hepatoma or liver metastases
If rheumatologic disorder is likely,
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).
Hepatomegaly without splenomegaly argues against rheumatologic disorders.
Physical Exam Finding Clinical Correlate
Oral ulcers Behcet disease, systemic lupus erythematosus [SLE]
Unequal pulses Takayasu arteritis
Lymphadenopathy SLE, RA, sarcoidosis
Rashes Sarcoidosis, SLE, adult Still disease
Epididymal nodule Periarteritis nodosa, SLE, and sarcoidosis
Step 2: First line testing (non-specific):
Laboratory Testing:
Complete blood count with differential
Routine blood chemistries, including liver enzymes and bilirubin
Urine analysis with microscopy and urine culture
Erythrocyte sedimentation rate (ESR) &C-reactive protein (CRP)
Three sets of blood cultures (from different sites, several hours apart, and prior to initiation of antibiotic
therapy)
Tuberculin skin test or interferon-gamma release assay
Imaging
Chest radiograph, abdominal-pelvic ultrasound
If the above laboratory work-up is negative, obtain a CT of chest, abdomen and pelvis with po/iv contrast
Step 3: If certain diagnosis is suspected :
A. If an infectious disease is suspected:
Second-Line Tests: Transthoracic echocardiography (TTE), sputum culture for AFB, HIV immunoassay,
Hepatitis A, B, and C serologies, RPR, ASO titer, serology for CMV, EBV or Brucellosis.
Third-Line Tests: Transesophageal echocardiography (TEE), lumbar puncture(LP), Sinus CT, Gallium scan
or FDG-PET/CT
B. If a non-hematologic malignancy is suspected:
Second-Line Tests: Mammography, Chest CT with contrast, Abdomen and pelvis CT with contrast,
Endoscopy, Bone Scan, Gallium Scan or FDG-PET/CT.
Third-Line Tests: MRI of the brain, Lymph node biopsy, Skin lesion biopsy, Liver biopsy, Endoscopic
biopsy, Exploratory Laparoscopy.
C. If a hematologic malignancy is suspected:
Second-Line Tests: Peripheral smear, serum protein electrophoresis.
Third-Line Tests: Bone marrow biopsy
D. If a rheumatologic disease is suspected:
Second-Line Tests: RF, ANA, cryoglobulin, ferritin
Third-Line Tests: Temporal artery biopsy, Lymph node biopsy
E. Venous Doppler studies should be obtained in relevant patients.
Treatment
Discontinue unnecessary medications.
If no source identified after extensive investigation, then watchful waiting is reasonable for patients who are
clinically well.
Empiric therapy with antibiotics or corticosteroids is discouraged, unless patient is clinically declining,
immunocompromised, or a potentially rapidly progressive diagnosis is strongly suspected (e.g., subacute
bacterial endocarditis with peripheral manifestations, miliary tuberculosis awaiting biopsy results, giant cell
arteritis).
Consider antipyretics if the patient has associated symptoms (headache, arthralgia, myalgia), although they
may alter fever patterns.
References:
[Link] DH. Approach to the adult with fever of unknown origin. UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA.
2023.
[Link] I, Finnigan NA. Fever of Unknown Origin. [Updated 2023 Aug 14]. In: StatPearls [Internet]. Treasure Island (FL):
StatPearls Publishing; 2023 Jan-. Available from: [Link]
[Link] DH, Weller PF, Thorner AR. Etiologies of fever of unknown origin in adults. Monografía en Internet]. Walthman
(MA): UpToDate. 2023.