“Fever of Unknown Origin”
(FUO)
Courtney Hebert, MD
Clinical Assistant Professor, Division of
Infectious Diseases
courtney.hebert@osumc.edu
Learning Objectives
 Define and describe the term “Fever of Unknown
Origin (FUO)”
 Recognize common infectious and non-infectious
etiologies of FUO
 Describe the infectious and non-infectious work-up
of patients diagnosed with FUO
 Describe the management of patients with FUO
Defining the term “FUO”
First formal definition (1961)
1.
Temperatures greater than 38.3°C or 101°F on
several occasions
2.
Duration of fever greater than 3 weeks
3.
Failure to reach diagnosis after 1 week in
hospital
Categories of FUO
Hayakawa 2012
Categories of FUO
Hayakawa 2012
Categories of FUO
Hayakawa 2012
Categories of FUO
Hayakawa 2012
Categories of FUO
Hayakawa 2012
Classic FUO
Etiologies fall into 5 general
categories
1.
2.
3.
4.
5.
Infection
Malignancy
Connective tissue Dz.
Miscellaneous
No diagnosis
MACKOWIAK, PHILIP A.,DURACK, DAVID T. - Mandell, Douglas, and
Bennett's Principles and Practice of Infectious Diseases, 779-789
Classic FUO
The Percentage of Patients with FUO
by Cause Over the Past 40 years.
Mourad, 2003
Arch Intern Med. 2003;163(5):545-551. doi:10.1001/archinte.163.5.545
Classic FUO
 Common infectious causes of FUO

Unrecognized abscess (ex: abdominal,
perinephric)

Endocarditis – less common than in past

HACEK organisms usually able to be cultured
with modern techniques

Difficult to culture organisms (ex:
Bartonella, Aspergillus, Coxiella, Brucella)

Tuberculosis

Histoplasmosis

Osteomyelitis
Classic FUO
 Common connective tissue causes of FUO

Adult Still’s disease

Fever, rash, arthritis

Rheumatoid Arthritis (RA)

Systemic Lupus Erythematosus (SLE)

Temporal Arteritis


>50 years old, headache, symptoms of PMR, high ESR
Polymyalgia Rheumatica (PMR)
Classic FUO
 Common malignancies associated with FUO

Lymphoma (most common cause)

Leukemia

Tumors metastatic to the liver

Renal cell carcinoma
Classic FUO
 Miscellaneous causes of FUO

Factitious Fever (ex: Fraudulent vs. Self-induced)

Drug fever (ex: Antibiotics, Antihistamines, NSAIDS)

Familial fever syndromes

Familial Mediterranean Fever

TNF-receptor associated periodic syndrome

Hyper- IgD syndrome.

Hemophagocytic syndrome

Inflammatory Bowel Disease (IBD)

Pheochromocytoma

Pulmonary embolism (PE)

Thrombotic Thrombocytopenic Purpura (TTP)

Thyroiditis
Nosocomial FUO
 Patients who have a fever start after at least 24 hours of
hospitalization
 Etiologies include:

Drug fever

Nosocomial infections

Post operative complications

Central fever (stroke)
Immune Deficient FUO
 Patients with significantly impaired immune response often
do not have traditional signs of inflammation
 This makes detection of infections more difficult
Neutropenic FUO
 Neutropenia = < 500 PMNs (absolute)
 Decreased mucosal defense
 Febrile neutropenic patients receive empiric courses of
broad spectrum antibiotics and often antifungal agents
Neutropenic FUO
Causes of Fever in
Patients with
Prolonged
Neutropenia Who
Are Receiving
Broad Spectrum
Antibiotics.
Corey NEJM 2002
HIV Related FUO
 Incidence of FUO has decreased since the introduction of
HAART
Abellan-Martinez, 2009
HIV Related FUO
 Common causes of HIV-Related FUO:

Mycobacterial disease

Pneumocystosis (PCP)

Cytomegalovirus (CMV)

Histoplasmosis

Lymphoma

Drug fever
Abellan-Martinez, 2009
Evaluation of FUO
 Comprehensive history

Verify fevers and establish pattern

Localizing symptoms?

Workplace?

Pets?

Recent travel?

History of connective tissue disease (CTD)?

History of cancer/immunosuppression?

Medications?

Drug use?

Familial fever syndromes?
Evaluation of FUO
Physical exam
Temporal artery in
elderly patient, sinus
tenderness
Evaluation of FUO
Physical exam
Listen for murmur, look for
stigmata of endocarditis
(Osler’s nodes, Janeway lesions,
conjunctival hemorrhage)
Evaluation of FUO
Physical exam
Lymphadenopathy,
Thyromegaly
Evaluation of FUO
Physical exam
Perirectal abscess
in neutropenia
Evaluation of FUO
Physical exam
Splenomegaly,
Hepatomegaly
Evaluation of FUO
Physical exam
Deep Vein
Thrombosis (DVT)
Evaluation of FUO
Physical exam
Skin, mucous
membranes, teeth
Evaluation of FUO
 Workup should be directed by patient’s symptoms and most
likely diagnosis
 Most should get the following laboratory studies:

Complete Blood Count (CBC) with Differential

Serum chemistries

Liver function tests

Urinalysis (UA)

Blood cultures

HIV Antibody

Chest X-Ray
 Selected serologies for infectious
causes (based on exposure history)
 Disseminated granulomatous
disease with abnormal CBC 
consider bone marrow biopsy (ex:
Disseminated Histoplasmosis)
Evaluation of FUO
 Imaging
Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 1011-1034; http://m.australianprescriber.com/magazine/21/3/76/9/
Evaluation of FUO
 Imaging
http://cancergrace.org/cancer-101/tag/pet-scans/; http://www.cmej.org.za/index.php/cmej/article/view/2796/3137
Evaluation of FUO
Mourad, 2003
Management of FUO
 Withhold therapy until the cause is found
 Exceptions:

Neutropenic Fever

Corticosteroids in suspected Temporal Arteritis

Unstable hospitalized patient
Outcome of FUO
 A review of the literature from 1966 – 2000 showed
a mortality rate of 12 – 35% for Classic FUO.

Higher mortality  If malignancy is identified

Lower mortality  If infection is identified
 If no cause is identified, 50 – 100% in these case
series have a spontaneous recovery!!!
Mourad, 2003
Summary of FUO
 The definition of classic FUO is temperature >101 °F for >3 weeks, and no
diagnosis after 3 days in the hospital or 3 clinic visits.
 Definition differs for patients with neutropenia, HIV or suspected
nosocomial onset.
 Causes of FUO are diverse, but can be categorized into infectious,
malignancy, connective tissue disease and miscellaneous causes.
 Comprehensive history and physical exam are an important first step in
FUO evaluation.
 Evaluation of FUO with laboratory test and imaging should be directed
towards the most likely causes based on the history and physical.
 The key to management of FUO is to withhold specific treatment (but
must note exceptions) until the cause is found.
Thank you!
Courtney Hebert, MD
E-mail:
courtney.hebert@osumc.edu
References
1.
Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine.
1961;40:1-30.
2.
Durack DT, Street AC. Fever of unknown origin--reexamined and redefined. Current clinical
topics in infectious diseases. 1991;11:35-51.
3.
Mackowiak PA, Durack DT. Fever of Unknown Origin. In: Mandell GL, Douglas RG, Bennett JE,
Dolin R, editors. Mandell, Douglas, and Bennett's principles and practice of infectious diseases.
6th ed. New York: Elsevier/Churchill Livingstone; 2005. p. 718-29.
4.
Corey L, Boeckh M. Persistent fever in patients with neutropenia. The New England journal of
medicine. 2002;346(4):222-4.
5.
Abellan-Martinez J, Guerra-Vales JM, Fernandez-Cotarelo MJ, Gonzalez-Alegre MT. Evolution of
the incidence and aetiology of fever of unknown origin (FUO), and survival in HIV-infected
patients after HAART (Highly Active Antiretroviral Therapy). European journal of internal
medicine. 2009;20(5):474-7.
6.
Hayakawa K, Ramasamy B, Chandrasekar PH. Fever of unknown origin: an evidence-based
review. The American journal of the medical sciences. 2012;344(4):307-16. Epub 2012/04/06.
7.
Mourad O, Palda V, Detsky AS. A comprehensive evidence-based approach to fever of
unknown origin. Archives of internal medicine. 2003;163(5):545-551.
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