1. “Fever of Unknown Origin” (FUO) Courtney Hebert, MD Clinical Assistant Professor, Division of Infectious Diseases courtney.hebert@osumc.edu

2. 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

3. 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

4. Categories of FUO Hayakawa 2012

5. Categories of FUO Hayakawa 2012

6. Categories of FUO Hayakawa 2012

7. Categories of FUO Hayakawa 2012

8. Categories of FUO Hayakawa 2012

9. Classic FUO Etiologies fall into 5 general categories 1. Infection 2. Malignancy 3. Connective tissue Dz. 4. Miscellaneous 5. No diagnosis MACKOWIAK, PHILIP A.,DURACK, DAVID T. - Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 779-789

10. 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

11. 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

12. 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)

13. Classic FUO  Common malignancies associated with FUO  Lymphoma (most common cause)  Leukemia  Tumors metastatic to the liver  Renal cell carcinoma

14. 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

15. 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)

16. Immune Deficient FUO  Patients with significantly impaired immune response often do not have traditional signs of inflammation  This makes detection of infections more difficult

17. Neutropenic FUO  Neutropenia = < 500 PMNs (absolute)  Decreased mucosal defense  Febrile neutropenic patients receive empiric courses of broad spectrum antibiotics and often antifungal agents

18. Neutropenic FUO Causes of Fever in Patients with Prolonged Neutropenia Who Are Receiving Broad Spectrum Antibiotics. Corey NEJM 2002

19. HIV Related FUO  Incidence of FUO has decreased since the introduction of HAART Abellan-Martinez, 2009

20. HIV Related FUO  Common causes of HIV-Related FUO:  Mycobacterial disease  Pneumocystosis (PCP)  Cytomegalovirus (CMV)  Histoplasmosis  Lymphoma  Drug fever Abellan-Martinez, 2009

21. 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?

22. Evaluation of FUO Physical exam Temporal artery in elderly patient, sinus tenderness

23. Evaluation of FUO Physical exam Listen for murmur, look for stigmata of endocarditis (Osler’s nodes, Janeway lesions, conjunctival hemorrhage)

24. Evaluation of FUO Physical exam Lymphadenopathy, Thyromegaly

25. Evaluation of FUO Physical exam Perirectal abscess in neutropenia

26. Evaluation of FUO Physical exam Splenomegaly, Hepatomegaly

27. Evaluation of FUO Physical exam Deep Vein Thrombosis (DVT)

28. Evaluation of FUO Physical exam Skin, mucous membranes, teeth

29. 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)

30. 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/

31. Evaluation of FUO  Imaging http://cancergrace.org/cancer-101/tag/pet-scans/; http://www.cmej.org.za/index.php/cmej/article/view/2796/3137

32. Evaluation of FUO Mourad, 2003

33. Management of FUO  Withhold therapy until the cause is found  Exceptions:  Neutropenic Fever  Corticosteroids in suspected Temporal Arteritis  Unstable hospitalized patient

34. 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

35. 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.

37. Thank you! Courtney Hebert, MD E-mail: courtney.hebert@osumc.edu

38. 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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