Fever of origin (FUO) as defined by Petersdorf and Beeson in 1961 is documentation of fever >38.3ᵒ C /100.9ᵒ F for more than 3 weeks duration, when the source of fever is not diagnosed during 3 days of hospital visits or 3 days of outpatient visits. HIV positive patients the duration taken is more than 4 weeks and for Paedriatic population it should be more than 8 days fever after history, physical examination data fail to reveal the cause.
Fever is caused due to exogenus pyrogens such as toxin, product of microbes which lead to secretion of endogenous factors like Cytokines, Interleukin 6, Interleukin 1, Interleukin L-11, Interferon gamma . These cytokines are produced by the macrophages and they cause hypothalamus to increase prostaglandin synthesis leading to fever.
History should include family history, ethnic background, travel history, animal exposure. History of exposure to animals includes specific test like Brucellosis, Psittacosis,Leptospirosis,Toxoplasmosis, Cat scratch disease, Q fever , Rat bite fever. History of travel may include need of malaria test.
To Diagnose cause of FUO, the fever has to documented and its characteristics need to be noted.Fever pattern like duration and timing of spikes is important in diagnosis like fever spikes in Malaria,Lymphoma,or Cyclical neutropenia is seen. Lymphoma (Hodgkin’s) and (Non-Hodgkin’s) can present with classic Pel-Ebstein fever characterized with intermittent febrile period lasting for days to weeks of afebrile period. Presence of morning spike fever suggests Tuberculosis, disseminated Salmonella infection and polyarteritis nodosum.
Two fever spike may happen with tuberculosis and malaria. Periodic fevers that lasts for days to week occur in children include cyclic neutropenia,familial Mediterranean disease, fever of pharyngitis and apthous stomatitis.
Physical examination may reveal other sign like Myalgias, headache, mental confusion, cardiovascular accident, nonproductive cough, vision disorders, fatigue, abdominal pain, back pain, neck pain according to the etiological factors causing the disease.
The most common cause of classic FUO in nonhospitalized patient is infections (bacterial, fungal , viral , parasitic ) neoplasms, hypersensitivity and autoimmune diseases, drugs. Cause in neutropenic (Absolute neutrophil count ANC <500) is fungal infection, perianal infection, bacterial infection, drugs and underlying disease. In elderly population it can be due to malignancy, infection like abdominal infections, Prostatitis, Tuberculosis, Sarcoidosis, Lupus, Still’s disease collagen vascular disease, drugs.
In HIV patients due to Tuberculosis, Mycobacterium avium complex, cryptococcal, fungal, lymphoma, drugs. Paedriatic age group due to infection most common respiratory tract infection, collagen vascular diseases, malignancy and drugs.
Laboratory test and evaluation include Routine test like CBC (complete blood cell count) CRP (C reactive protein), ESR (Erythrocyte sedimentation rate) raised, Chest X-ray, Blood chemistry and Serial blood culture (three blood culture over 48 hrs) should be drawn to detect bacterial, fungal, mycobacterial infections, urine cultures. Newer platforms like molecular diagnostics, rapid diagnostics like MALDITOF (matrix assisted laser desorption ionization-time of flight mass spectrometry) can be used to diagnose Bacterial, fungal, viral aetiology. CBC (Complete blood cell count) may show leukopenia,anemia,thrombocytosis.
Serum protein electrophoresis if immunological etiology is suspected. Thyroid, liver, kidney function test, Rheumatoid factor and Anti-nuclear antibody test when suspected need to be done.
In general noninvasive technique should be used to diagnose FUO, however if not diagnosed invasive diagnosis should be done like computer tomography scans (CT scan), bone marrow biopsy, liver biopsy and rarely abdominal laparotomy.
Empiric treatment of FUO, is not recommended and etiological diagnosis should be made. For Infections suspected,broad spectrum antibiotic covering gram positive , gram negative , anaerobic infections should be initiated . In neutropenic patients anti-fungal prophylaxis should also be included. If malignancy is suspected specific treatment need to be initiated. In HIV positive patient empiric therapy of antimycobacterial therapy may be useful.In autoimmune disorders Steroids are indicated.