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Fever of Unknown Origin,SORT KEY RECOMMENDATIONS FOR PRACTICE. Clinical recommendation rating References, A comprehensive history and physical examination should be performed if there are no C 15 17 21. localizing signs and symptoms in patients with prolonged febrile illness. Potentially diagnostic clues should be sought during the history and physical examination to C 15 17. guide further evaluation of prolonged febrile illness. In patients with a prolonged febrile illness a minimum diagnostic workup should be C 1 2 4 7 15 20 27. performed before classifying the disease process as a fever of unknown origin. Erythrocyte sedimentation rate and C reactive protein levels should be measured in the initial C 5 15 28 29. workup of a patient who has prolonged febrile illness without a clear source. In patients who have a fever of unknown origin with an elevated erythrocyte sedimentation C 15 37 40. rate and or C reactive protein levels and who have not received a diagnosis after initial. evaluation 18F fluorodeoxyglucose positron emission tomography scan with or without. computed tomography may be useful in reaching a diagnosis. If noninvasive diagnostic tests are unrevealing then the invasive test of choice is a tissue C 2 3 5 15 19 22. biopsy because of the relatively high diagnostic yield Depending on clinical clues this may 27 41. include liver lymph node temporal artery or bone marrow biopsy. A consistent good quality patient oriented evidence B inconsistent or limited quality patient oriented evidence C consensus disease oriented. evidence usual practice expert opinion or case series For information about the SORT evidence rating system go to http www aafp org afpsort. Common causes of FUO are listed in Table 2 6 15 23 Typ Figure 1 outlines a diagnostic approach to patients with. ical subgroups used in the differential for classical FUO prolonged febrile illness and FUO 1 2 4 7 15 20 23 27. are infection 20 to 40 malignancy 20 to 30 Hospitalization may be considered at any time during. noninfectious inflammatory diseases 10 to 30 the evaluation especially if the patient exhibits signs of. miscellaneous 10 to 20 and undiagnosed up to a critical illness Approximately 12 to 35 of patients. 50 1 4 6 14 18 22 24 Noninfectious inflammatory diseases die from an FUO related cause generally infection. commonly include connective tissue diseases vascu or malignancy yet of those whose conditions remain. litides and granulomatous diseases 16 17 In developed undiagnosed most recover or have a benign course with. countries the noninfectious inflammatory diseases and a good prognosis 5 22. undiagnosed groups comprise a higher proportion of. COMMON INFECTIONS, FUO cases 5 10 15 17 Underdeveloped countries have higher. rates of infection and neoplasm 6 24 Drug fever is impli At the initial encounter testing for common infections. cated in 1 to 3 of FUO cases16 Table 320 21 25 26 should include a complete blood count with differential. electrolyte panel liver enzymes urinalysis with culture. From Prolonged Febrile Illness to FUO, Because there are no guidelines to the approach of the. febrile patient most evaluation recommendations are Table 1 Definitions of Fever of Unknown Origin. based on expert opinion 17 On initial presentation most. clinicians perform a history and physical examination in Original 1961 3 Temperature 101 F 38 3 C on several. pursuit of an infection When there are no clear localiz separate occasions. ing signs or symptoms clinicians should expand on the Fever lasting longer than three weeks. Evaluation of at least one week in the, patient s symptoms and historical information looking.
for potentially diagnostic clues to guide the evaluation. Revised 1991 7 Temperature 101 F on several separate. Table 4 17 20 25 27 This is a continuous iterative pro occasions. cess 19 21 Potentially diagnostic clues lead to a diagnosis Fever lasting longer than three weeks. in 62 of patients although clues can be misleading Evaluation of at least three outpatient visits. because they are found in 97 of patients 15 17 or three days in inpatient care. If no potentially diagnostic clues are found a mini Qualitative2 6 10 17 Temperature 101 F documented clinically. on several separate occasions,mum diagnostic workup should be performed Infec. Appropriate initial diagnostic workup,tions predominate early in FUO diagnoses and the. inpatient or outpatient does not reveal, longer FUO remains undiagnosed the less likely it is etiology of fever. caused by an infection 27 After infections the etiology of. FUO transitions to noninfectious inflammatory diseases Information from references 2 3 6 7 and 10 through 17. and malignancies which can guide subsequent testing. 92 American Family Physician www aafp org afp Volume 90 Number 2 July 15 2014. Fever of Unknown Origin, Table 2 Common Causes of Fever of Unknown Table 3 Medications that Can Cause Fever. Origin of Unknown Origin, Subgroup Cause Anticonvulsants Cardiovascular drugs.
Barbiturates Captopril Capoten,Infection Bacterial. Carbamazepine Hydralazine, 20 to 40 Abdominal or pelvic abscesses Tegretol Hydrochlorothiazide. Dental abscesses Phenytoin Dilantin Methyldopa,Endocarditis Antihistamines Nifedipine Procardia. Sinusitis Cimetidine Tagamet Procainamide, Tuberculosis especially extrapulmonary Ranitidine Zantac Quinidine. disseminated,Antimicrobials Nonsteroidal anti inflammatory.
Urinary tract infection,Carbapenems drugs,Cephalosporins Ibuprofen. Cytomegalovirus,Erythromycin Salicylates,Epstein Barr virus. Isoniazid Sulindac Clinoril,Malignancy Colorectal cancer. Minocycline Minocin Others,20 to 30 Leukemia,Nitrofurantoin Allopurinol Zyloprim. Lymphoma Hodgkin and non Hodgkin,Furadantin Heparin.
Noninfectious Connective tissue diseases Penicillins Meperidine Demerol. inflammatory Adult Still disease Rifampin Phenothiazines. disease 10,Rheumatoid arthritis Sulfonamides,Systemic lupus erythematosus. Granulomatous disease The literature does not identify individual drugs in these classes. Crohn disease Information from references 20 21 25 and 26. Sarcoidosis,Vasculitis syndromes,Giant cell arteritis. However a more recent prospective study found that the. Polymyalgia rheumatica temporal arteritis,Miscellaneous Drug induced. chance of establishing a diagnosis was higher in patients. 10 to 20 Factitious fever,who had an elevated CRP level and ESR 15. Thromboembolic disease Procalcitonin is a newer marker specific for bacterial. Thyroiditis infection In multiple studies procalcitonin has been. shown to have a specificity ranging from 70 to 98, Information from references 6 and 15 through 23 with a higher specificity for bacterial infection than.
other markers 28 31 32 It may be helpful in distinguishing. between fevers with a bacterial cause vs noninfectious. blood culture and chest radiography If there is no clear inflammatory diseases but its role in the workup of FUO. source of infection then further testing should follow is currently undefined 28 32. Erythrocyte sedimentation rate ESR and C reactive,MALIGNANCIES AND NONINFECTIOUS INFLAMMATORY. protein CRP are nonspecific acute phase reactants that. are routinely part of the evaluation of febrile patients 5 28. An extremely elevated ESR 100 mm per hour or greater If the diagnosis remains elusive tests targeting malig. suggests etiologies such as abdominal or pelvic abscess nancies and noninfectious inflammatory diseases. osteomyelitis and endocarditis However ESR does should be considered Elevated lactate dehydrogenase. not help discriminate between active autoimmune dis levels can be indicative of infectious and malignant. ease and infection and malignancies and noninfectious causes of FUO including malaria lymphoma and leu. inflammatory diseases can cause an elevated ESR and kemia 15 21 Measurement of ferritin levels may also be. CRP level In one review an ESR of 100 mm per hour helpful 33 An elevated ferritin level in prolonged febrile. or greater had a high specificity for malignancy 96 illness may indicate malignancy especially myeloprolif. and infection 97 and its positive predictive value was erative disorders and other noninfectious inflammatory. 90 29 A normal ESR has a high negative predictive value diseases such as systemic lupus erythematosus or tem. for temporal arteritis 28 30 An ESR that is not elevated poral arteritis 21 33 One study established a ferritin level. has no diagnostic value and does not rule out neoplas of 561 ng per mL 1 261 pmol per L as the optimal cut. tic or other disorders 27 CRP level is a sensitive marker off value to predict that FUO was due to a noninfectious. for infection and inflammation but it is not sensitive cause 22 Extreme elevation of ferritin levels greater than. enough to discriminate between disease processes 28 1 000 ng per mL 2 247 pmol per L can point to adult. July 15 2014 Volume 90 Number 2 www aafp org afp American Family Physician 93. Fever of Unknown Origin, Table 4 Potentially Diagnostic Clues for Patients with. Fever of Unknown Origin,Clues Possible diagnoses,creatine kinase level can suggest other infec. Historical,tious sources and common noninfectious,inflammatory disease etiologies such as. Fresh water exposure Leptospirosis,systemic lupus erythematosus rheumatoid.
Living conditions e g homeless Tuberculosis, shelter arthritis and vasculitides Previous testing. Occupational exposures sick Cytomegalovirus Epstein Barr virus ESR complete blood count electrolyte panel. contacts e g with hospitalized tuberculosis chest radiography urinalysis blood culture. patients children may be repeated periodically to evaluate for. Pets wild animals Brucellosis trends as the illness evolves Age appropriate. Recent travel especially to Region specific e g Q fever for parts or potentially diagnostic clue guided cancer. areas with endemic diseases of Europe, domestic and abroad screening should be performed e g colonos. Family history copy in patients 50 years or older, Hereditary febrile conditions Familial Mediterranean fever Abdominal and pelvic ultrasonography. Medical history are often recommended in the initial workup. Abdominal disorders Alcoholic hepatitis cirrhosis Crohn because of availability low cost and lack of. disease radiation exposure 15 After the initial evalua. History of transfusions Hepatitis B or C HIV tion is complete and if there is no diagnosis. Malignancy Metastatic disease the patient is considered to have FUO and a. Psychiatric illness Factitious fever secondary evaluation should be considered. Recent hospitalization Nosocomial infection,Risk taking behaviors Secondary Evaluation. Intravenous drug abuse Abscess endocarditis osteomyelitis Several diagnostic algorithms have been. Sexually transmitted infection HIV suggested for FUO but few are supported by. evidence from prospective studies 17 Region,Surgical history.
specific serologic tests more advanced,Presence of prostheses Osteomyelitis. radiologic studies and more invasive diag,nostic procedures can be guided by poten. Characteristic rashes e g erythema Adenovirus herpes simplex virus HIV. multiforme petechiae meningococcemia tick borne illness tially diagnostic clues One review found. Conjunctivitis or uveitis Adult Still disease leptospirosis that noninvasive procedures led to most of. systemic lupus erythematosus the diagnoses whereas of the invasive pro. Hepato or splenomegaly palpable Alcoholic liver disease carcinoma cedures biopsies had the highest diagnostic. abdominal masses cytomegalovirus Epstein Barr virus yield 4. leukemia lymphoma,Other recommended blood tests at this. Joint swelling or pain with Inflammatory bowel disease Lyme. movement disease systemic lupus erythematosus phase include cryoglobulins elevated in. Lymphadenopathy Cat scratch disease cytomegalovirus endocarditis systemic lupus erythematosus. Epstein Barr virus HIV leukemias and lymphomas 15 35 complement. studies serologic tests peripheral smear, HIV human immunodeficiency virus serum protein electrophoresis and thyroid. Information from references 17 through 20 25 and 27 function studies Note that serologic tests. are helpful only if there are potentially diag,nostic clues and if the patient lives in or has.
Still disease 34 Infection is the most common reason ESR visited an area where the suspected disease is prevalent 15. is extremely elevated but if there is no evidence of infec. tious causes clinicians should consider malignancy IMAGING STUDIES. renal disease and inflammatory disorders if the ESR is Chest abdominal or pelvic computed tomography CT. 100 mm per hour or greater 29 may be useful in the secondary evaluation In one study. Testing for antinuclear antibodies rheumatoid fac of patients with FUO chest and abdominal CT had high. tor human immunodeficiency virus Epstein Barr sensitivity 82 and 92 respectively and were rec. virus cytomegalovirus purified protein derivative or ommended if the initial evaluation was unrevealing 15. interferon gamma release assay and antineutrophil CT specificity ranged from 60 to 70 consistent with. cytoplasmic antibodies as well as measurement of the other case series 15 16 Echocardiography is recommended. 94 American Family Physician www aafp org afp Volume 90 Number 2 July 15 2014. Fever of Unknown Origin,Evaluation for Prolonged Febrile Illness. and Fever of Unknown Origin,Patient with temperature 101 F. 38 3 C on several occasions, value 93 and negative predictive value 100 39 40 A. hybrid of CT and 18F fluorodeoxyglucose positron emis. Comprehensive history and physical examination sion tomography has a higher diagnostic yield sensitivity. looking for potentially diagnostic clues,of 56 to 100 specificity of 75 to 81 18 The 18F. fluorodeoxyglucose has better uptake and is cleared more. Clues found Order appropriate rapidly than older modalities e g gallium Ga 67 citrate. diagnostic tests but it is costly and not widely available 14. Perform minimum diagnostic workup BIOPSIES, Complete blood count chest radiography urinalysis and urine culture.
Liver lymph node or temporal artery biopsy may help. Erythrocyte sedimentation rate C reactive protein electrolyte panel. liver enzymes, establish a definitive diagnosis 3 19 A prospective study. Lactate dehydrogenase creatine kinase blood cultures antinuclear of 192 patients found that biopsies produced up to a. antibodies rheumatoid factor serologic testing Epstein Barr virus 35 diagnostic yield about 10 to 35 especially if. cytomegalovirus human immunodeficiency virus performed later in the evaluation when infection is less. Purified protein derivative interferon gamma release assay abdominal. likely and malignancies and noninfectious inflamma. and pelvic ultrasonography or computed tomography, tory diseases are more common 2 Liver biopsy with a. diagnostic yield between 14 and 17 5 19 can reveal. Diagnosis evident Complete appropriate granulomatous hepatitis and determine its cause which. evaluation and treatment, No could be infectious inflammatory or neoplastic pro. cesses 22 27 Lymph node biopsy is most useful in diagnos. Meets definition of fever,of unknown origin, ing lymphoma infectious diseases and granulomatous. diseases 19 27 In patients 55 years or older temporal arte. ritis causes more than 15 of cases of FUO so biopsy. Additional diagnostic workup should be considered 5 15 18. Consider measuring ferritin level cryoglobulins antineutrophil. cytoplasmic antibodies thyroid testing complement studies. Bone marrow biopsy is diagnostically useful particu. peripheral blood smear serum protein electrophoresis larly with neoplasm and infectious disease especially. If available 18F fluorodeoxyglucose positron emission tomography tuberculosis 19 27 One study of 280 hospitalized febrile. computed tomography patients found that bone marrow biopsy was helpful in. Tissue biopsy as indicated lymph node liver temporal artery bone reaching a diagnosis in nearly 25 of the 130 patients. who underwent biopsy 41 Conversely bone marrow, aspiration and culture have a diagnostic yield of only.
Figure 1 Suggested evaluation for prolonged fever and 0 to 2 3 5 15 22 41. fever of unknown origin, Information from references 1 2 4 through 7 15 through 20 23 and 27 Empiric Therapy and Referral. Empiric trials of antibiotics or steroids rarely establish. if there are clinical indications of endocarditis 5 20 Venous a diagnosis and are discouraged in the management. Doppler ultrasonography is indicated for suspected of patients with FUO unless there are clinical indica. thromboembolism 20 Magnetic resonance imaging of the tions 5 17 19 21 22 Consultation with a subspecialist e g infec. aortic arch and great vessels of the neck was shown to be tious disease specialist rheumatologist hematologist. helpful when vasculitis was suspected 36 oncologist is appropriate at any point in the evaluation. Nuclear imaging studies are noninvasive image the Data Sources A PubMed search was completed using the key terms. whole body and can localize a potential infectious or fever of unknown origin FUO pyrexia of unknown origin and inflamma. inflammatory cause for FUO 5 14 19 37 40 Recently 18F flu tory markers The search included reviews case series meta analyses and. randomized controlled trials Additional searches included the Cochrane. orodeoxyglucose positron emission tomography tech, database Essential Evidence Plus the Agency for Healthcare Research. nology has been evaluated for guiding further invasive and Quality evidence reports and the National Guideline Clearinghouse. testing especially in patients who have an elevated ESR or Additional references were identified from the articles reviewed Search. CRP level 14 37 The 18F fluorodeoxyglucose is taken up by dates November 28 2011 February 8 2012 and April 18 2014. inflammatory and cancer cells because of their high rate The views expressed in this manuscript are those of the authors and do. of glucolysis 14 18 37 Several studies examining this method not reflect the official policy or position of the Department of the Army. in patients with FUO found diagnostic yields ranging Department of Defense or the U S government. from 16 to 69 15 37 38 with a high positive predictive The authors thank Diane Kunichika for her assistance with the manuscript. July 15 2014 Volume 90 Number 2 www aafp org afp American Family Physician 95. Fever of Unknown Origin, 19 Hayakawa K Ramasamy B Chandrasekar PH Fever of unknown origin. The Authors an evidence based review Am J Med Sci 2012 344 4 307 316. 20 Roth AR Basello GM Approach to the adult patient with fever of. ELIZABETH C HERSCH COL MC USA is the deputy commander for clini unknown origin Am Fam Physician 2003 68 11 2223 2228. cal services at General Leonard Wood Army Community Hospital in Fort. 21 Cunha BA Fever of unknown origin clinical overview of classic and cur. Leonard Wood Mo At the time the article was written Dr Hersch was a. rent concepts published correction appears in Infect Dis Clin North Am. staff family physician and geriatrician at the Tripler Army Medical Cen 2008 22 2 xv Infect Dis Clin North Am 2007 21 4 867 915 vii. ter Family Medicine Residency Program Honolulu Hawaii and a clinical. 22 Hayakawa K Ramasamy B Chandrasekar PH Fever of unknown origin. assistant professor of family medicine at the Uniformed Services Univer. an evidence based review Am J Med Sci 2012 344 4 307 316. sity of the Health Sciences Bethesda Md, 23 Kim SE Kim UJ Jan MO et al Diagnostic use of serum ferritin levels to. ROBERT C OH LTC MC USA is a sports medicine fellow at the National differentiate infectious and noninfectious diseases in patients with fever. Capital Consortium in Bethesda Md and a clinical assistant professor of of unknown origin Dis Markers 2013 34 3 211 218. family medicine at the Uniformed Services University of the Health Sci 24 Hirschmann JV Fever of unknown origin in adults Clin Infect Dis. ences At the time the article was written Dr Oh was the service chief for 1997 24 3 291 300. the Department of Family Medicine at Tripler Army Medical Center 25 Tolia J Smith LG Fever of unknown origin historical and physical. clues to making the diagnosis Infect Dis Clin North Am 2007 21 4. Address correspondence to Elizabeth C Hersch COL MC USA Gen. 917 936 viii, eral Leonard Wood Army Community Hospital 4430 Missouri Ave Ft.
26 Johnson DH Cunha BA Drug fever Infect Dis Clin North Am 1996. Leonard Wood MO 65473 Reprints are not available from the authors. 10 1 85 91, 27 Cunha BA Fever of unknown origin focused diagnostic approach. REFERENCES based on clinical clues from the history physical examination and labo. 1 Erg n l O Willke A Azap A Tekeli E Revised definition of fever of ratory tests Infect Dis Clin North Am 2007 21 4 1137 1187 xi. unknown origin limitations and opportunities J Infect 2005 50 1 1 5 28 Limper M de Kruif MD Duits AJ Brandjes DP van Gorp EC The diag. 2 Vanderschueren S Knockaert D Adriaenssens T et al From prolonged nostic role of procalcitonin and other biomarkers in discriminating infec. febrile illness to fever of unknown origin the challenge continues Arch tious from non infectious fever J Infect 2010 60 6 409 416. Intern Med 2003 163 9 1033 1041 29 Fincher RM Page MI Clinical significance of extreme elevation of. 3 Petersdorf RG Beeson PB Fever of unexplained origin report on 100 the erythrocyte sedimentation rate Arch Intern Med 1986 146 8. cases Medicine Baltimore 1961 40 1 30 1581 1583, 4 Gaeta GB Fusco FM Nardiello S Fever of unknown origin a system 30 Smetana GW Shmerling RH Does this patient have temporal arteritis. atic review of the literature for 1995 2004 Nucl Med Commun 2006 JAMA 2002 287 1 92 101. 27 3 205 211 31 Kim MH Lim G Kang SY Lee WI Suh JT Lee HJ Utility of procalcitonin. 5 Mourad O Palda V Detsky AS A comprehensive evidence based as an early diagnostic marker of bacteremia in patients with acute fever. approach to fever of unknown origin Arch Intern Med 2003 163 5 Yonsei Med J 2011 52 2 276 281. 545 551 32 Naito T Mizooka M Mitsumoto F et al Diagnostic workup for fever of. 6 Zenone T Fever of unknown origin in adults evaluation of 144 cases in unknown origin a multicenter collaborative retrospective study BMJ. a non university hospital Scand J Infect Dis 2006 38 8 632 638 Open 2013 3 12 e003971. 7 Durack DT Street AC Fever of unknown origin reexamined and rede 33 Cunha BA Fever of unknown origin FUO diagnostic importance of. fined Curr Clin Top Infect Dis 1991 11 35 51 serum ferritin levels Scand J Infect Dis 2007 39 6 7 651 652. 8 Whitehead TC Davidson RN Pyrexia of unknown origin changing epi 34 Fautrel B Le Mo l G Saint Marcoux B et al Diagnostic value of fer. demiology Curr Opin Infect Dis 1997 10 2 134 138 ritin and glycosylated ferritin in adult onset Still s disease J Rheumatol. 9 Konecny P Davidson RN Pyrexia of unknown origin in the 1990s time 2001 28 2 322 329. to redefine Br J Hosp Med 1996 56 1 21 24 35 de Kleijn EM van Lier HJ van der Meer JW Fever of unknown origin. 10 Goto M Koyama H Takahashi O Fukui T A retrospective review of 226 FUO II Diagnostic procedures in a prospective multicenter study of. hospitalized patients with fever Intern Med 2007 46 1 17 22 167 patients The Netherlands FUO Study Group Medicine Baltimore. 11 Habibzadeh F Yadollahie M Time for a change in the definition of fever 1997 76 6 401 414. of unknown origin J Infect 2008 57 2 166 167 36 Wagner AD Andresen J Raum E et al Standardised work up pro. 12 Chang JC Why do we still use the term FUO Arch Intern Med 2003 gramme for fever of unknown origin and contribution of magnetic. 163 17 2102 resonance imaging for the diagnosis of hidden systemic vasculitis Ann. 13 Bryan CS Fever of unknown origin the evolving definition Arch Intern Rheum Dis 2005 64 1 105 110. Med 2003 163 9 1003 1004 37 Pelosi E Skanjeti A Penna D Arena V Role of integrated PET CT with. 14 Bleeker Rovers CP van der Meer JW Oyen WJ Fever of unknown origin 18F FDG in the management of patients with fever of unknown origin. Semin Nucl Med 2009 39 2 81 87 a single centre experience Radiol Med 2011 116 5 809 820. 15 Bleeker Rovers CP Vos FJ de Kleijn EM et al A prospective multicenter 38 Kubota K Nakamoto Y Tamaki N et al FDG PET for the diagnosis of. study on fever of unknown origin the yield of a structured diagnostic fever of unknown origin a Japanese multi center study Ann Nucl Med. protocol Medicine Baltimore 2007 86 1 26 38 2011 25 5 355 364. 16 de Kleijn EM Vandenbroucke JP van der Meer JW Fever of unknown 39 Balink H Collins J Bruyn GA Gemmel F F 18 FDG PET CT in the diag. origin FUO I A prospective multicenter study of 167 patients with nosis of fever of unknown origin published correction appears in Clin. FUO using fixed epidemiologic entry criteria The Netherlands FUO Nucl Med 2010 35 11 895 Clin Nucl Med 2009 34 12 862 868. Study Group Medicine Baltimore 1997 76 6 392 400 4 0 Keidar Z Gurman Balbir A Gaitini D Israel O Fever of unknown origin. 17 Knockaert DC Vanderschueren S Blockmans D Fever of unknown ori the role of 18F FDG PET CT J Nucl Med 2008 49 12 1980 1985. gin in adults 40 years on J Intern Med 2003 253 3 263 275 41 Hot A Jaisson I Girard C et al Yield of bone marrow examination in. 18 Varghese GM Trowbridge P Doherty T Investigating and managing diagnosing the source of fever of unknown origin Arch Intern Med. pyrexia of unknown origin in adults BMJ 2010 341 C5470 2009 169 21 2018 2023. 96 American Family Physician www aafp org afp Volume 90 Number 2 July 15 2014.


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