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fever of unknown origin (FUO)

- fever of > 38.3 C (101 F) measured on several occasions with a duration of > 2-3 weeks without a diagnosis - also requires 2 outpatient visits or 3 days of hospitalization [3] Etiology: 1) 180 different diseases have been documented as a cause of FUO (also see causes of fever of unknown origin) 2) most cases are unusual manifestations of common diseases 3) infection, connective tissue disease & malignancies account for the majority of cases 4) infection a) intra-abdominal abscess, pelvic abscess b) tuberculosis (especially extrapulmonary TB) c) endocarditis 1] especially HACEK group, Bartonella, Legionella, Coxiella burnetii, Chlamydia psittaci & fungi 2] hold blood cultures for 2 weeks d) ascending cholangitis e) viral infection - HIV1 infection - infectious mononucleosis (EBV) most common viral cause in childeren [11] - cytomegalovirus infection [3] f) endemic mysosis g) C difficile colitis h) chronic sinusitis i) complicated urinary tract infection [3] 5) malignancy a) lymphoma b) leukemia c) renal cell carcinoma d) hepatocellular carcinoma 6) connective tissue disease a) polymyalgia rheumatica b) giant cell arteritis c) rheumatoid arthritis - adult onset Still's disease d) systemic lupus erythematosus e) vasculitis - polyarteritis nodosa 7) granulomatous diseases a) sarcoidosis b) granulomatous hepatitis c) inflammatory bowel disease d) Wegener's granulomatosis 8) endocrine disease - hyperthyroidism - subacute thyroiditis 9) hereditary periodic fever syndrome a) fever-free intervals of at least 14 days b) hyperimmunoglobilin D syndrome c) familial hibernian fever d) Muckle-Wells syndrome e) familial Mediterranean fever 10) other a) septic thrombophlebitis b) deep vein thrombosis or pulmonary embolus c) chronic sinusitis d) drug fever 11) factitious (patient may not have fever) 12) observations - in 10% of cases, no source of fever is found - 30-50% of patients may not receive a specific diagnosis - the longer a fever persists without a diagnosis, the less likely an infectious or malignant origin [3] History: 1) documented fever 2) travel history 3) exposure a) occupation b) exposure to animals c) drugs (days-weeks after initiation of new drug) d) transfusions e) surgery f) tuberculosis 4) sexual history 5) genetic background Clinical manifestations: 1) lymphadenopathy 2) cardiac murmur 3) skin lesions a) skin rash b) Janeway lesions, Osler's nodes, subconjunctival petechiae may portend serious underlying illnees [3] 4) hepatomegaly 5) splenomegaly 6) uveitis 7) retinal lesions 8) repeated examinations may reveal new &/or changing signs & symptoms Laboratory: 1) complete blood count (CBC) 2) repeated blood cultures (>= 3 sets) 3) urinalysis & urine culture 4) liver function tests 5) serum TSH 6) antinuclear antibody (ANA) 7) rheumatoid factor (RF) 8) erythrocyte sedimentation rate, serum CRP 9) HIV testing 10) serum protein electrophoresis 11) Epstein-Barr serology - monospot for infectious mononucleosis 12) cytomegalovirus serology 13) serology for syphilis: RPR, VRDL 14) tuberculin skin testing (PPD) vs Quantiferon TB testing 15) consider ANCA is specific cases [7] Special laboratory: 1) echocardiogram 2) pulmonary function testing: - decreased DLCO suggests restrictive lung disease such as sarcoidosis 3) colonoscopy 4) biopsy a) bone marrow biopsy & culture if hematologic abnormalities seen on laboratory testing [3] - yields diagnosis in 24% of cases [5] b) percutaneous liver biopsy c) biopsy of other tissues directed by clinical picture 1] skin 2] lymph nodes 3] blood vessels - temporal artery biopsy 4] kidney 5) specialized tests directed by history & clinical findings Radiology: 1) chest X-ray 2) abdominal & thoracic or total body computed tomography (CT) - CT of abdomen & pelvis with & without contrast [3] - 18F-FDG PET-CT may contribute to diagnosis in 75% of patients [13] 3) abdominal ultrasound 4) upper GI series with small bowel follow-through 5) barium enema 6) gallium scintigraphy (Ga-labeled leukocyte imaging) - indium-labeled leukocyte imaging is relatively insensitive in working up FUO Management: 1) discontinue non-essential medications 2) direct therapy at underlying etiology a) non-specific therapy should not be instituted until the source of the fever is identified b) therapeutic trials may be misleading by producing temporary relief 3) many patients will recover without therapy - patients with idiopathic FUO generally have good prognosis with resolution of fever within several months [3] - 96% of patients < 35 years of age & 68% of patients > 65 will eventually become free of fever without therapy - after 3 weeks, careful evaluation, & 2 ambulatory visits, no further testing or treatment is indicated 4) patients debilitated by symptoms a) non-steroidal anti-inflammatory agent NSAID b) steroids may be tried if: 1] patient fails NSAIDs 2] etiology unlikely to be infectious 5) antibiotics a) use of antibiotics is discouraged b) if endocarditis is suspected & patient is deteriorating, antibiotic therapy may be reasonable, but should be be stopped is cultures are negative 6) consider naproxen for paraneoplastic or prostaglandin-mediated fever

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causes of fever of unknown origin

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References

  1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 845-47
  2. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 780-84
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2021 - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. Journal Watch 23(14):109, 2003 Vanderschueren S et al From prolonged febrile illness to fever of unknown origin: the challenge continues. Arch Intern Med 163:1033, 2003 PMID: 12742800
  5. Hot A et al Yield of bone marrow examination in diagnosing the source of fever of unknown origin. Arch Intern Med 2009 Nov 23; 169:2018. PMID: 19933965
  6. Mourad O et al A comprehensive evidence-based approach to fever of unknown origin. Arch Intern Med. 2003 Mar 10;163(5):545-51. PMID: 12622601
  7. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010 - Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
  8. Bleeker-Rovers CP, Vos FJ, de Kleijn EM et al A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore). 2007 Jan;86(1):26-38. PMID: 17220753
  9. Hayakawa K, Ramasamy B, Chandrasekar PH Fever of unknown origin: an evidence-based review. Am J Med Sci. 2012 Oct;344(4):307-16. Review. PMID: 22475734
  10. Mulders-Manders C, Simon A, Bleeker-Rovers C. Fever of unknown origin. Clin Med (Lond). 2015 Jun;15(3):280-4. PMID: 26031980 Free PMC Article
  11. NEJM Knowledge+ Question of the Week. Aug 20, 2019 https://knowledgeplus.nejm.org/question-of-week/4127/ - Chow A , Robinson JL. Fever of unknown origin in children: a systematic review. World J Pediatr 2010 Dec 31; 7:5. PMID: 21191771 - Antoon JW, Potisek NM, Lohr JA. Pediatric fever of unknown origin. Pediatr Rev 2015 Sep; 36:380. PMID: 26330472
  12. Haidar G, Singh N Fever of Unknown Origin. N Engl J Med 2022; 386:463-477. Feb 3. PMID: 35108471 https://www.nejm.org/doi/full/10.1056/NEJMra2111003
  13. Buchrits S, McNeil R, Avni T et al. The contribution of 18F FDG PET-CT for the investigation of fever of unknown origin and inflammation of unknown origin. Am J Med 2024 Jul; 137:629. PMID: 38499136 https://www.amjmed.com/article/S0002-9343(24)00174-8/fulltext