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“Fever of Unknown Origin” (FUO)
Courtney Hebert, MD
Clinical Assistant Professor, Division of Infectious Diseases
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. Infection2. Malignancy3. Connective tissue Dz.4. Miscellaneous5. No diagnosis
MACKOWIAK, PHILIP A.,DURACK, DAVID T. - Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 779-789
Classic FUO
Arch Intern Med. 2003;163(5):545-551. doi:10.1001/archinte.163.5.545
The Percentage of Patients with FUO by Cause Over the Past 40 years.
Mourad, 2003
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.
Fever of Unknown Origin Quiz
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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