1. Jan 27, 2011 Dr. Joyce Pickering Fever of Unknown Origin

2. Key points Definition Causes Workup Outcomes

3. Definition Fever greater than 38.3 on several occasions, lasting at least 3 weeks, and after negative workup Original definition – after one week of inpatient investigation 3 days in hospital, 3 outpatient visits After a certain battery of tests Workup usually starts earlier than 3 weeks.

4. Causes Most common causes? Will vary depending on the definition E.g., if a CT abdomen is included as one of the battery of tests, then you will have less cases of intraabdominal abcess or malignancy who remain undiagnosed after the initial battery of tests. Will also vary depending on geography – e.g., infections more common in southern climates.

5. Copyright restrictions may apply. Mourad, O. et al. Arch Intern Med 2003;163:545-551. The percentage of patients with fever of unknown origin by cause over the past 40 years

6. 2 major recent studies Bleeker-Rovers, Vos, De Kleijn et al. A Prospective Multicenter Study on Fever of Unknown Origin: The Yield of a Structured Diagnostic Protocol. Medicine, Jan. 2007 73 patients with FUO recruited between 2003 and 2005 in the Netherlands. Vanderschueren, Knockaert, Adriaenssens et al. From Prolonged Febrile Illness to Fever of Unknown Origin: The Challenge Continues. Archives of Internal Medicine, May 2003 290 immunocompetent patients in Belgium referred for fever between 1990 and 1999.

7. Note: both studies excluded immunocompromised patients including HIV+ patients. Belgium studied excluded nosocomial FUOs – not clear if Dutch study excluded these.

8. Initial workup History and Physical Dutch series – Average 15 diagnostic clues per patient by careful history, physical exam and initial blood tests BUT 81% of these clues were misleading! Remember: Travel Pets/Occupation Drugs/Immunosuppression Belgian series – History and evolution led to Dx in 23% of cases. Biopsy led to diagnosis in 25% of cases

9. Initial workup (Dutch study) CBC, Blood cultures x 3, LFTs, SMA-7, U/A and urine C and S, CXR. ESR/CRP LDH HIV RF, CK, SPEP CT abd or ultrasound. PPD/quantiferon (do monospot if young)

10. 2 nd level workup (if first not diagnostic) Cryglobulins, PET scan Bone marrow biopsy, temporal artery biopsy in patients > 55 years, fundoscopy, chest and abd CT (if not already done). Not clear if PET adds more than gallium scanning.

11. One of the purposes of the Dutch study was to study which tests were useful.

12. Clues from initial blood tests Abnormal LFTs – present in 27% Rarely contributes to a final diagnosis Does not predict a diagnostic liver biopsy ANA, ANCA – usually false positive Only contributed if the patient had other signs or symptoms suggested a vasculitis Once 3 blood cultures done, further cultures were not helpful.

13. Remember: all these tests can have false positives CXR: done in 73 patients: helpful in six, false positive in 8 Chest CT – done in 46 patients: helpful in 12, false positive in 17 Abdominal CT – done in 60 patients: helpful in 12, false positive in 17 PET scan – done in 70 patients: helpful in 23 and false positive in 10.

14. Final Diagnoses: Belgian study: 50% - no diagnosis 20% - non infectious inflammatory disease Eg. Adults Still’s disease, temporal arteritis 10% - neoplasms 10% - infections 10% - miscellaneous

15. Final Diagnoses: Dutch Study: 51% no diagnosis 22% non infectious inflammatory disease 16% infection 7% neoplasm 4% miscellaneous

16. NB: Studies from more southern countries show a higher rate of TB, and diseases such as leishmaniasis.

17. Outcomes: Dutch study: 51% had no diagnosis – of these 43% resolved spontaneously 14% got better with nonspecific treatment with NSAIDS or steroids 40% had persistent fever 3% (one patient) died Median follow up was 12 mos.

18. Subcategories Intermittent fevers (fever free period of at least two weeks in between fevers) more likely to remain undiagnosed. FUO in HIV patients 80% due to infections High rate of mycobacterial infection, MAC or TB 10% due to tumors 10% undiagnosed Neutropenic FUO – bacteria most common, then fungal infections more common after 7 days. Gram neg infections probably most serious, but increasing rate of gram positive infections Many other possible causes Underlying disease, transfusions, drugs, graft rejection etc.

19. Famous cases Mrs. K. 55 female from China Persistent fever x 9 months Intermittent back pain, swelling around eye Extensive investigations – several liver biopsies, bone biopsy, TTNA of lung all showed nonspecific inflammation. High (but fluctuating) ESR and CRP Trial of antibiotics and then steroids Dx: on open lung biopsy – NK lymphoma.

20. Mrs. T Fever, posterior headache, weight loss, anemia, high CRP, ESR. Blood cultures, bone/gallium, CT chest/abd neg. Fever resolved in hospital Lost partial vision after D/C Diagnosis: Temporal arteritis

21. Dr. M. Physician who had recently spent time in Bangladesh Persistent fever over 2 weeks Malaria smears neg x 2 U/A, Urine C and S positive – had pyelonephritis

22. Take home lessons Not necessary to hospitalize patients to work up FUO. Watch out for false positives, both on history, physical and lab results when investigating. Up to half of patients never have a diagnosis made. These patients have a good prognosis HIV patients with FUO are very different and have a high rate of infections.