3. HISTORY
• Petersdorf & Beeson: Original definition in 1961.
• Exclusion of immunocompromised individuals.
• Elimination of in-hospital evaluation.
4. DEFINITION
• Fever > 38.3*C (101*F) on at least two occasions
• Illness duration > 3 weeks
• No known immunocompromised state
• Diagnosis that remains uncertain after a thorough history-taking,
physical examination, and the following obligatory investigations:
• CBC, ESR, CRP, LFT, RFT, Electrolytes, LDH, CK, Ferritin, ANA, RF, Urinalysis,
Protein electrophoresis, Blood and Urine Cultures, Chest X-Ray, Abdominal
Ultrasonography & Tuberculin Skin Test.
13. APPROACH
• Most important step in diagnostic work-up is the search for PDCs
(Potentially Diagnostic Clues).
• PDCs are defined as all localizing signs, symptoms, and potentially
abnormalities pointing toward a diagnosis.
14. APPROACH: History
• Fever pattern
• Duration
• Previous medical history with present and recent drug use.
• Family history
• Sexual history
• Country of origin and recent or remote travel.
• Unusual environmental exposures including animal contacts.
15. APPROACH: Examination
• Complete physical examination
• Special attention to the eyes, lymph nodes, temporal arteries,
liver, spleen, sites of previous surgery, entire skin surface, and
mucous membranes.
16. DIAGNOSTIC TESTS
• Before initiating tests, antibiotics and glucorticoid treatment
should be stopped.
• All obligatory tests to be done.
• Rarely lead to a diagnosis of FUO in the absence of PDCs.
• Cryoglobulins are a valuable screening test in the absence of
specific symptoms.
• Multiple blood cultures
• Unusual organism testing
• Histoplasma or Legionella will require specialized media.
• Repeated cultures are useless in the absence of PDCs.
17. DIAGNOSTIC TESTS
• CSF analysis to be done for FUO with headache.
• Herpes simplex, Cryptococcus neoformans and Mycobacterium tuberculosis.
• Tuberculin Sensitivity Test: False negative in Miliary Tuberculosis,
malnutrition or immunosuppression.
• Interferon y release assay is the other option.
• Miliary Tuberculosis: Liver biopsy for acid-fast smear, culture and PCR has
highest diagnostic yield. Bone marrow and lymph node can also be
considered.
• Echocardiography, endoscopy and bronchoscopy have low
diagnostic yield.
• In the absence of PDCs, fundoscopy may be useful.
18. DIAGNOSTIC TESTS: Scintigraphy
• Performed when ESR or CRP are elevated after first stage tests do
not lead to a diagnosis.
• Noninvasive method allowing delineation of foci in all parts of the
body on the basis of functional changes in tissues.
• Ga-citrate, In- or Tc-labelled leukocyte scintigraphy.
• Scintigraphy is a better option than CT or MRI.
19. DIAGNOSTIC TESTS: FDG-PET
• F-flurodeoxyglucose (FDG) positron emission tomography (PET) has
become an established imaging method in FUO.
• FDG accumulates in tissues with high rates of glycolysis (malignant
cells and activated leukocytes).
• Higher resolution, greater sensitivity in chronic low-grade
infection and high degree of accuracy.
• No difference in uptake of vasculitis, infection, inflammation or
malignancy.
• FDG-PET/CT better.
20. LATER-STAGE DIAGNOSTIC TESTS
• Pathology and/or culture of biopsy specimens found through
scintigraphy or FDG-PET.
• Second stage testing if there is no diagnosis.
• CT abdomen and chest.
• Temporal Artery biopsy.
21. TREATMENT: Antimicrobials & ATT
• Empirical therapuetic trials should be avoided except when
patient’s condition is rapidly deteriorating.
• Antibiotics
• Hemodynamic instability or neutropenia
• Antituberculous therapy
• TST positive or presence of granulomatous disease and sarcoidosis is
unlikely.
• 6 weeks.
22. TREATMENT: Colchicine, NSAIDs &
Glucocorticoids
• Colchicine for familial Mediterranean fever.
• NSAIDs as supportive treatment if diagnosis remains elusive after
completion of later-stage investigations.
• Glucocorticoids in giant cell arteritis and polymyalgia rheumatica
• NSAIDs and glucocorticoids should be avoided unless ifectious
diseases and lymphoma are ruled out.
23. TREATMENT: Anakinra
• Recombinant form of naturally occuring Interleukin-1 receptor
antagonist.
• Extremely effective in treating many autoinflammatory
syndromes.
• Familial Mediterranean fever, cryopyrin-associated periodic syndrome,
tumor necosis factor receptor-associated periodic syndrome, hyper-IgD
syndrome.
• Therapeutic trial with Anakinra can be considered in patients not
diagnosed even after later-stage diagnostic tests.
24. PROGNOSIS
• FUO-related mortality rates have continuously declined over
recent decades.
• Most of the mortality is accounted by malignancy.
• Empirical therapy is rarely required in stable patients.
25. REFERENCES
• Harrison’s Principles of Medicine
• Goldman-Cecil Medicine
• API Textbook of Medicine 2017
• www.uptodate.com
• www.pubmed.com
26. THANK VERY MUCH
“Humanity has three great enemies: fever, famine and wars. Of these by far the
greatest, by far the most terrible is fever” – Sir William Osler
