“Fever of Unknown Origin” (FUO) Courtney Hebert, MD Clinical Assistant Professor, Division of...

“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. 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

Thank you!

Courtney Hebert, MDE-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.

Survey

We would appreciate your feedback on this module. Click on the button below to complete a brief survey. Your responses and comments will be shared with the module’s author, the LSI EdTech team, and LSI curriculum leaders. We will use your feedback to improve future versions of the module.

The survey is both optional and anonymous and should take less than 5 minutes to complete.

Survey