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Fever of Unknown Origin

Morning Report August 9, 2005 Hili Morillas, MD

Fever > 38.3 on several occasions Fever lasting more than 3 weeks No diagnosis despite 1 week of inpatient workup

Potential Etiologies
Based on patient population Classical Immunodeficient (Neutropenic) Nosocomial HIV related

Classic FUO
Fever > 38.3 Duration greater than 3 weeks Evaluation for 3 weeks as an outpatient or 3 days in hospital

Classic FUO
Infection Malignancy Collagen vascular diseases

Nosocomial FUO
Fever > 38.3 Patient hospitalized > 24 hours, but no fever on admission Evaluation for at least 3 days

Nosocomial FUO
Clostridium difficile Drug induced Pulmonary embolism Septic thrombophlebitis Sinusitis

Neutropenic FUO
Fever > 38.3 ANC 500 or less Evaluation for at least 3 days

Neutropenic FUO
Opportunistic bacterial infections Herpes Virus Aspergillosis Candidiasis

Fever > 38.3 Duration > 4 weeks (outpatient) or > 3 days (inpatient) HIV infection confirmed

CMV MAC PCP Drug induced Kaposis Sarcoma Lymphoma


Tuberculosis (especially extrapulmonary) Abdominal abscesses Pelvic abscesses Dental abscesses Endocarditis Osteomyelitis Sinusitis Cytomegalovirus Epstein-Barr virus Human immunodeficiency virus Lyme disease Prostatitis Sinusitis

As duration of fever increases, infectious etiology decreases Malignancy and factitious fevers are more common in patients with prolonged FUO.


Chronic leukemia Lymphoma Metastatic cancers Renal cell carcinoma Colon carcinoma Hepatoma Myelodysplastic syndromes Pancreatic carcinoma Sarcomas


Adult Still's disease Polymyalgia rheumatica Temporal arteritis Rheumatoid arthritis Rheumatoid fever Inflammatory bowel disease Reiter's syndrome Systemic lupus erythematosus Vasculitides


Drug-induced fever Complications from cirrhosis Factitious fever Hepatitis (alcoholic, granulomatous, or lupoid) Deep venous thrombosis Sarcoidosis

Failure to reach a diagnosis is not uncommon 20% of cases remain undiagnosed Even if extensive investigation does not identify a cause, these patients still have favorable outcomes.

Comprehensive History Physical Exam

Confirm fever and document pattern

Laboratory Data


Recent travel Exposure to pets and other animals Sexual history Work environment Contact with other people with similar symptoms Family history Past medical history list of medications

Include OTC

Physical Exam
Skin Mucus membranes Lymphadenopathy Organomegaly


A cost-effective individualized approach is essential in the evaluation of these patients to prevent performing inappropriate tests.

Diagnosis of Fever of Unknown Origin

Diagnostic Testing
CBC LFTs ESR Urinalysis Blood cultures Further testing should be based on abnormalities in the initial workup


PPD testing is inexpensive screening tool that should be used on all FUO patients that do not have a known positive reaction

If initial testing is inconclusive- more specific testing should be performed based on clinical suspicion Serologies CT Ultrasounds MRI Nuclear Medicine Scans

Chest radiograph

CT of abdomen or pelvis with contrast agent

Tuberculosis, malignancy, Pneumocystis carinii pneumonia Abscess, malignancy

Gallium 67 scan

Indium-labeled leukocytes

Infection, malignancy Occult septicemia

Technetium Tc 99m

MRI of brain

Acute infection and inflammation of bones and soft tissue Malignancy, autoimmune conditions Malignancy, inflammation Bacterial endocarditis Venous thrombosis

PET scan

Transthoracic or transesophageal echocardiography

Venous Doppler study


More invasive testing, such as LP or biopsy of bone marrow, liver, or lymph nodes, should be performed only when clinical suspicion shows that these tests are indicated or when the source of the fever remains unidentified after extensive evaluation. When the definitive diagnosis remains elusive and the complexity of the case increases, an infectious disease, rheumatology, or oncology consultation may be helpful.