Differential Diagnosis

The differential diagnosis of FUO generally is broken into four major subgroups: infections, malignancies, autoimmune conditions, and miscellaneous. Several factors may limit the applicability of research literature on FUO to everyday medical practice. These factors include the geographic location of cases, the type of institution reporting results (e.g., community hospital, university hospital, ambulatory clinic), and the specific subpopulations of patients with FUO who were studied. Despite these limiting factors, infection remains the most common cause of FUO in study reports.


Of the many infectious diseases that are associated with FUO, tuberculosis (especially in extrapulmonary sites) and abdominal or pelvic abscesses are the most common.13Intraabdominal abscesses are associated with perforated hollow viscera (as occurs in appendicitis), diverticulitis, malignancy, and trauma. Other common infections that should be considered as the source of FUO include subacute bacterial endocarditis, sinusitis, osteomyelitis, and dental abscess.As the duration of fever increases, the likelihood of an infectious etiology decreases. Malignancy and factitious fever are more common diagnostic considerations in patients with prolonged FUO.


Because of a substantial increase in the elderly population, as well as advances in the diagnosis and treatment of diseases common in this population, malignancy has become a common etiologic consideration in elderly patients. Malignancies that sometimes are difficult to diagnose, such as chronic leukemias, lymphomas, renal cell carcinomas, and metastatic cancers, often are found in patients with FUO.


Rheumatoid arthritis and rheumatic fever are inflammatory diseases that used to be commonly associated with FUO, but with advances in serologic testing, these conditions usually are diagnosed more promptly. At this time, adult Still’s disease and temporal arteritis have become the most common autoimmune sources of FUO because they remain difficult to diagnose even with the help of laboratory testing.

Multisystem inflammatory diseases such as temporal arteritis and polymyalgia rheumatica have emerged as the autoimmune conditions most frequently associated with FUO in patients older than 65 years. Elderly patients who present with symptoms consistent with temporal arteritis associated with an elevation of the erythrocyte sedimentation rate should be referred for temporal artery biopsy.


Many unrelated pathologic conditions can present as FUO, with drug-induced fever being the most common. This condition is part of a hypersensitivity reaction to specific drugs such as diuretics, pain medications, antiarrhythmic agents, antiseizure drugs, sedatives, certain antibiotics, antihistamines, barbiturates, cephalosporins, salicylates, and sulfonamides.

Complications from cirrhosis and hepatitis (alcoholic, granulomatous, or lupoid) are also potential causes of FUO. Deep venous thrombosis, although a rare cause of FUO, must be considered in relevant patients, and venous Doppler studies should be obtained. Factitious fever has been associated with patients who have some medical training or experience and a fever persisting longer than six months. Failure to reach a definitive diagnosis in patients presenting with FUO is not uncommon; 20 percent of cases remain undiagnosed. Even if an extensive investigation does not identify a cause for FUO, these patients generally have a favorable outcome.

Common Etiologies of Fever of Unknown Origin

Tuberculosis (especially extrapulmonary)
Abdominal abscesses
Pelvic abscesses
Dental abscesses
Epstein-Barr virus
Human immunodeficiency virus
Lyme disease
Chronic leukemia
Metastatic cancers
Renal cell carcinoma
Colon carcinoma
Myelodysplastic syndromes
Pancreatic carcinoma
Autoimmune conditions
Adult Still’s disease
Polymyalgia rheumatica
Temporal arteritis
Rheumatoid arthritis
Rheumatoid fever
Inflammatory bowel disease
Reiter’s syndrome
Systemic lupus erythematosus
Drug-induced fever
Complications from cirrhosis
Factitious fever
Hepatitis (alcoholic, granulomatous, or lupoid)
Deep venous thrombosis

Agents Commonly Associated with Drug-Induced Fever
 Allopurinol (Zyloprim)
 Captopril (Capoten)
 Cimetidine (Tagamet)
 Clofibrate (Atromid-S)
 Hydralazine (Apresoline)
 Hydrochlorothiazide (Esidrix)
 Meperidine (Demerol)
 Methyldopa (Aldomet)
 Nifedipine (Procardia)
 Nitrofurantoin (Furadantin)
 Phenytoin (Dilantin)
 Procainamide (Pronestyl)


Cherry DK, Woodwell DA, National ambulatory medical care survey.

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