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Fever of Unknown Origin

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FEVER OF UNKNOWN ORIGIN

Definition:
- Fever higher than 38.3C on several occasions
- Duration of fever at least three weeks
- Uncertain diagnosis after one week of study in hospital or - Temp >38.5
- Duration > 2 weeks
- Undiagnosed

Etiology
1. Noninfectious inflammatory disease
- Adult Still’s disease: daily fevers, arthritis, evanescent rash
- Giant cell arteritis: headache, loss of vision, symptoms of polymyalgia rheumatica, fever, anemia, high ESR, jaw claudication
- Polyarteritis nodosa
- Takayasu’s arteritis
- Wegener’s
- Mixed cryoglobulinemia
- Venous thrombosis and thromboembolism
- Hematoma
- Hyperthyroid, acute thyroiditis
- Pheochromocytoma, adrenal insufficiency
- Alcoholic hepatitis: fever, hepatomegaly, jaundice, anorexia,

2. Infection
- Tuberculosis: most common infection in FUO, PPD positive in 90% of FUO infective endocarditis
- Rare infections: leptospirosis, psittacosis, tularemia, melioidosis, secondary syphilis, disseminated gonoccocemia, chronic meningococcemia, visceral leishmaniasis, whipples disease, yersiniosis

3. Malignancy
- Lymphoma, especially NHL
- Leukemia
- Renal cell carcinoma: microscopic hematuria,
- Hepatocellular carcinoma
- Myelodysplastic syndromes
- Multiple myeloma
- Atrial myxomas: arthralgia, emboli, hyperglobulinemia

4. Miscellaneous
- Drug fever: stimulate an allergic or idiosyncratic reaction, affecting thermoregulation (sulfonamides, penicillins, nitrofurantoin, vancomycin, antimalarials, H1 and H2 blockers, barbiturates, phenytoin, iodides, NSAIDs and salicylates, hydralazine, methyldopa, quinidine, procainamide, antithyroid drugs, digoxin, aminoglycosides)
- Factitious fever
- Disordered heat homeostasis - hypothalamic dysfunction
- Dental abscess
- Hereditary periodic fever syndromes: mediterranean fever, tumor necrosis factor receptor 1 associated periodic syndrome, hyper-IgD syndrome, muckle-wells, familial cold autoinflammatory syndrome

5. No Diagnosis (51%)

Diagnostic Approach
1. History and Physical - Travel, animal exposure, immunosuppression, localized symptoms, drug and toxin history

2. Diagnostic Testing
- Erythrocyte sedimentation rate and C-reactive protein: may help establish more serious underlying cause of FUO, debatable
- Serum lactate dehydrogenase, PPD, HIV, three routine blood cultures, rheumatoid factor, creatinine phosphokinase, heterophile antibody test, antinuclear antibodies, serum protein electrophoresis, CT scan of abdomen, CT scan of chest, - nuclear scans (FDG-PET): cannot offer diagnosis but may help localize site for further investigation
- biopsy: liver, lymph node, temporal artery, polyarteritis nodosa, pleural, pericardial, bone marrow

3. Therapeutic trials with antibiotics or glucocorticoids - rarely establishes a diagnosis and should be avoided

Outcome
Generally good prognosis
(Bleeker-Rovers CP. Et al) Among the 37 patients with no diagnosis who were followed for at least six months, 16 spontaneously recovered, 5 recovered with nonsteroidal antiinflammatory drugs or glucocorticoids, 15 had persistent fever, and 1 died.

References

Bleeker-Rovers CP, Vos FJ, de Kleijn EMHA, Mudde AH, Dofferhoff TS, Richter C, Smilde TJ, Krabbe PFM, Oyen WJG, and van der Meer JWM. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore). 2007 Jan;86(1):26-38.

Mourad O, Palda V, and Detsky A. A comprehensive evidence-based approach to fever of unknown origin. Arch Internal Med. 2003 Mar 163:545-551

E.M. Becerra Nakayo, A.M. García Vicente, A.M. Soriano Castrejón, J.A. Mendoza Narváez, M.P. Talavera Rubio, V.M. Poblete García, J.M. Cordero García, Analysis of cost-effectiveness in the diagnosis of fever of unknown origin and the role of 18F-FDG PET–CT: A proposal of diagnostic algorithm, Revista Española de Medicina Nuclear e Imagen Molecular (English Edition), Volume 31, Issue 4, July–August 2012, Pages 178-186

Algorithms:
Bleeker-Rovers CP, et al. (2007)

Mourad O. et al. (2003)

E.M. Becerra Nakayo (2012)

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