1. Fever of Unknown Origin AIMGP Seminar Series Dr. Katina Tzanetos February 2007

2. References Mourad, O., et al. A Comprehensive Evidenced- Based Approach to Fever of Unknown Origin. Arch Inter Med 163: March 10, 2003. Roth, A. and Basello, G. Approach to the Adult Patient with Fever of Unknown Origin. American Family Physician 68 (11), 2223. Up To Date. – Approach to the adult with fever of unknown origin – Etiologies of fever of unknown origin in adults * Much of this talk based on very helpful article by Mourad et al. – Highly recommended

3. Case Discussion – Based on Real Patient 28-year old female, born in Canada, parents from Hong Kong 2.5 week history of fever 40.0C or higher Only other symptom is possible rash on lower legs – intermittent, tender, red nodules Works in bank Non-smoker, non-drinker Only medication is OCP

4. Take a minute to discuss… Does she fit the criteria for Fever of Unknown Origin Why or why not?

5. Fever of Unknown Origin - Definition Classic definition – Temperature higher than 38.3C – Several occasions – Cause obscure after 1-week of in-patient evaluation Current definition – recognizes acceptability of out-patient in place of in-patient investigations

6. Case Discussion Based on short duration and absence of investigations patient does not fit diagnostic criteria If fever persists, should pursue diagnosis Her fever persists – What aspects of the history and physical examination do you focus on during this initial visit?

7. Four Proposed Categories of FUO Based on potential etiology of FUO All require temperature > 38.3C Categorization be especially helpful in organizing an “approach” to patient evaluation – Classic – Nosocomial – Immune-deficient (neutropenic) – HIV-related

8. Classic Category of FUO Definition: – Duration > 3 weeks, evaluation of at least 3 outpatient visits or 3 days in-hospital Common etiologies: – Infection, malignancy, CVD This category will be the focus of this talk

9. Nosocomial Category of FUO Definition: – Hospitalization of at least 24 hrs with no fever on admission, evaluation of at least 3 days Common etiologies: – C.Difficile, drugs, PE, septic thrombophlebitis, sinusitis (intubated patients)

10. Immune-deficient (neutropenic) Category of FUO Definition: – Neutrophil count < 500/mm 3, evaluation of at least 3 days Etiologies: – Opportunistic bacterial infections, aspergillosis, candidiasis, herpes virus

11. HIV-Associated Category of FUO Definition: – Duration of at least 4 weeks for outpatients and 3 days for inpatients, HIV confirmed Etiologies: – Cytomegalovirus, MAI, Pneumocystis, drugs, Kaposi’s, lymphoma

12. Etiology and Epidemiology of Classic FUO Infections: Most common cause accounting for 1/3 of cases – TB; Most common infection in non-elderly adults –PPD positive in less than 50% of pts with TB and FUO, Sputum samples positive in only ¼ of patients – Abscesses Usually in abdomen or pelvis with some pre-disposing cause (e.g. recent surgery, diabetes, biliary tract disease, recent UTI) – Other infections: Osteomyelitis, endocarditis (esp. in pts with recent antibiotic use or HACEK organisms) Malignancy: Second most common cause – Lymphoma (esp. non-Hodgkin’s), Leukemia, Renal cell, HCC, other metastasis to liver CVD: Third most common cause – Adult Still’s disease in younger patients and giant cell arteritis in older patients

13. Diagnostic Approach - History History – Travel – Exposures to toxins, sick persons, animals – Immunosuppression – Localizing symptoms – Look for subtle findings: eg. Jaw claudication, nocturia with prostatitis Degree of fever, nature of fever curve, apparent toxicity, and response to antipyretics not specific enough to guide management

14. Diagnostic Approach – Physical Examination Repeated examination may be needed Careful attention to skin, mucous membranes, lymph and abdominal system Ask pts to record and measure temperature daily Yield from history and physical examination unknown

15. Back to the case… Thorough history and physical non- contributory except for intermittent skin lesions Given what you know thus far, what investigations would you order?

16. Diagnostic Approach – Laboratory Investigations Suggested minimal diagnostic work-up to qualify as FUO has varied over the years Recent article by Mourad et al suggests following as minimal: – History and physical examination – CBC and differential – Blood film reviewed by hematopathologist – Routine chemistry including LDH, bilirubin, liver enzymes – Urinalysis and microscopy – ANA, RH factor – HIV – CMV IgM; heterophil test if suspicious for Mononucleosis – Q-fever serology (if risk exists) – CXR – Hepatitis serology (if abnormal liver enzymes)

17. Diagnostic Approach – Investigations and the Evidence Abdominal CT – Useful to look for abdominal lymphoma and abscess – Diagnostic yield in case series 19% – Clinical follow-up showed that only 1/32 patients with normal scans had an intra- abdominal cause for FUO

18. Diagnostic Approach – Investigations and the Evidence Nuclear Imaging: – For localizing inflammatory or infectious focus – Technetium scans likely have best test characteristics overall and should be test of choice Technetium studies: specificity 93%, sensitivity 40- 75%; PLR 5.7-12.5 Indium-labeled WBC scans: specificity 69%-86%, sensitivity 45%-82% Gallium scans: (limited studies)

19. Diagnostic Approach – Investigations and the Evidence Duke criteria for endocarditis: – Endocardities: 1-5% of all cases of FUO – Sensitivity 82%, specificity 99% Liver Biopsy: – Diagnostic yield 14%-17% regardless of whether abnormal physical exam or liver enzymes exist – Complications in FUO from biopsy only 0.32% at most – Recommended

20. Diagnostic Approach – Investigations and the Evidence Temporal artery biopsy – Large studies comprised of elderly with FUO lacking – Arteritis cause of FUO ~16% of pts (All comers) – Safe, recommended in elderly with FUO Leg dopplers – DVT cause of FUO ~ 2-6% of pts – Safe, easy to do, recommended

21. Diagnostic Approach – Investigations and the Evidence Bone Marrow Examination – Diagnostic yield of culture 0-2% – Not recommended in immunocompetent pts Abdominal exploration – Role of surgery in post-CT era uncertain Empiric Therapy (antibiotics, anti-TB, steroids) – Not studied – Not recommended

22. Proposed Diagnostic Algorithm Mourad, O. et al. Arch Intern Med 2003;163:545-551.

23. Back to the case… CBC and differential, electrolytes, BUN, creatinine, Ca/Mg/Ph all normal Liver enzymes very slightly elevated then normalized (AST 68  normal, ALT 78  normal), bilirubin, ALP normal Multiple blood cultures: no growth ESR 39 Hepatitis, Lyme, PPD, Mononucleosis, Q-fever, HIV serology all negative, ANA, RF negative CT thorax and abdomen normal 2D Echo normal Leg dopplers negative Skin biopsy: unremarkable epidermis and dermis, no subcutaneous material obtained; lesions resolved

24. Back to the case… Fever of > 40C continued for more than 4 weeks No diagnosis despite multiple out-pt visits and a short in-hospital stay Debated about going to bone marrow biopsy versus liver biopsy Decided on nuclear scan However, pt was given short course of oral antibiotics by family MD, symptoms resolved, pt cancelled all further tests and follow-up appointments with us and is doing fine

25. Conclusions from Case Given our modern-day advances, prognosis in patients who truly have no diagnosis after extensive recommended work-up is very good (most sinister diagnoses are discovered) In some cases, spontaneous resolution occurs, in others, watchful waiting is necessary (but often frustrating) – 1930s: > 30% of FUO with no diagnosis died – Today: 50-90% or more recover spontaneously