II. Types
- Classic Fever of Unknown Origin
- Daily or Intermittent Fever >= 38.3 C (101 F)
- Duration for 3 consecutive weeks
- Qualitative FUO definition does not set an absolute minimum duration
- No source by clinical evaluation
- Hospital evaluation for 3 days (previously 7) or
- Intensive outpatient evaluation for 7 days or
- Three outpatient visits
-
Nosocomial Fever of Unknown Origin
- Daily or Intermittent Fever >= 38.3 C (101 F)
- Hospitalized >1 day without fever on admission
- Fever evaluation of 3 days of more
-
Immune-Deficient Fever of Unknown Origin
- Daily or Intermittent Fever >= 38.3 C (101 F)
- Neutrophil Count <500 per mm3
- Fever evaluation of 3 days of more
-
HIV-Associated Fever of Unknown Origin
- Daily or Intermittent Fever >= 38.3 C (101 F)
- Outpatient fever >4 weeks or
- Inpatient fever >3 days
III. Causes
IV. History
V. Exam
VI. Labs
- First Line
- Complete Blood Count (CBC) with manual differential
- Basic metabolic panel (e.g. Chem8)
- Liver Function Tests
- Blood Cultures (3 sets)
- Urinalysis with Urine Culture
- Markers of inflammation or infection
- Erythrocyte Sedimentation Rate (ESR)
- Very high ESR (e.g. >100 mm/h) suggests significant cause such as abdominal abscess, Osteomyelitis, endocarditis
- Consider cancer, renal disease or inflammatory disease if ESR very high but no infectious cause identified
- C-Reactive Protein (C-RP)
- Procalcitonin
- Procalcitonin level > 0.5 mg/dl is associated with severe Bacterial Infections
- Lactate Dehydrogenase
- Serum Ferritin
- Serum Ferritin >561 ng/ml may be consistent with noninfectious cause of FUO
- Serum Ferritin >1000 ng/ml may be consistent with Adult Still's Disease
- Cryoglobulins (second-line test)
- Increased in endocarditis, Systemic Lupus Erythematosus, Leukemia, Lymphoma
- Erythrocyte Sedimentation Rate (ESR)
- Common infection Screening Tests
- Monospot (consider EBV titer and CMV titer)
- Purified Protein Derivative (PPD) or TB Quantiferon (Interferon gamma release assay)
- Negative test does not exclude active pulmonary tuberculosiw
- HIV Test
- Viral Hepatitis A, B and E
- Autoimmune labs to consider
- Other tests to consider
- Thyroid Stimulating Hormone (TSH)
- Peripheral Smear
- Serum Protein Electrophoresis (see indications below)
- Biopsies to consider
- Skin biopsy
- Consider when atypical skin lesions accompany fever
- Liver biopsy
- Consider for evaluation of malignancy or noninfectious inflammatory condition
- Lymph Node biopsy
- Temporal artery biopsy
- Consider in suspected Temporal Arteritis (accounts for 15% of FUO over age 55 years)
- Bone Marrow Biopsy
- Consider in cancer, Tuberculosis and other infection
- Skin biopsy
VII. Imaging
- First-line
- Chest XRay
- Abdominal and pelvic Ultrasound (consider)
- Initial screening at low cost and without radiation exposure
- Second-line
- Other imaging with specific indications
- Echocardiogram
- Endocarditis
- Venous extremity Doppler Ultrasound
- MRI Aortic arch and Great Vessels
- Vasculitis evaluation
- Echocardiogram
VIII. Evaluation: Subsequent to consider
- Infectious cause suspected
- Second line tests
- AFB Sputum Cultures
- Rapid Plasmin Reagin (RPR)
- HIV Test
- ASO Titer
- Third line tests
- Transesophageal Echocardiogram (may start with Transthoracic Echocardiogram)
- Evaluate for endocarditis
- Lumbar Puncture
- Sinus CT
- Gallium Ga 67 Scan or 18F Fluorodeoxyglucose PET Scan
- Transesophageal Echocardiogram (may start with Transthoracic Echocardiogram)
- Second line tests
- Non-Hematologic Malignancy suspected
- Second line tests
- Third line tests
- Brain MRI
- Enlarged Lymph Node biopsy
- Skin lesion biopsy
- Liver biopsy
- Exploratory laparoscopy
- Hematologic Malignancy suspected
-
Autoimmune Condition suspected
- Rheumatoid Factor
- Antinuclear Antibody
- Antineutrophil Cytoplasmic Antibodies (ANCA)
- Creatine Kinase
- Consider temporal artery biopsy
- Consider Lymph Node biopsy
IX. Differential Diagnosis: Occult Bacteremia
- Consider hospitalization if fever >2 weeks
- Risk factors
- Age over 50 years
- Diabetes Mellitus
- Complete Blood Count: Leukocytosis and Left Shift
- Erythrocyte Sedimentation Rate >30
- Toxic appearance
- Immunocompromised patients
- Valvular heart disease
- Intravenous Drug Abuse
- References
X. Management
- Consider hospitalization (especially for signs of Critical Illness)
- Follow specific protocols that apply (e.g. Neutropenic Fever)
XI. Prognosis
- The majority of patients recover from FUO or follow a benign course
- Spontaneous resolution in 70%
- However, 12-35% of patients die from the cause of FUO
XII. References
- Claudius in Majoewsky (2012) EM: Rap 12(11): 9
- Libman in Noble (2001) Primary Care Medicine, p. 194
- Mackowiak in Mandell (2000) Infectious Disease, p. 622
- Cunya (1996) Infect Dis Clin North Am 10:111-27 [PubMed]
- David (2022) Am Fam Physician 105(2): 137-43 [PubMed]
- Hersch (2014) Am Fam Physician 90(2): 91-6 [PubMed]
- Mourad (2003) Arch Intern Med 163:545-51 [PubMed]
- Roth (2003) Am Fam Physician 68:2223-8 [PubMed]
Images: Related links to external sites (from Bing)
Related Studies
Definition (MSH) | Fever in which the etiology cannot be ascertained. |
Concepts | Sign or Symptom (T184) |
MSH | D005335 |
ICD10 | R50 , R50.9 |
SnomedCT | 206758001, 206764008, 158162001, 7520000 |
English | Unknown Origin Fever, Unknown Origin Fevers, PUO Pyrexia of unknown origin, Pyrexia of unknown orig.NOS, Pyrexia of unknown origin NOS, [D]Fever of unknown origin, [D]Pyrexia of unknown orig.NOS, [D]Pyrexia of unknown origin, [D]Pyrexia of unknown origin NOS, [D]Pyrexia of unknown origin (context-dependent category), [D]Pyrexia of unknown origin NOS (context-dependent category), fever of unknown origin, fever of unknown origin (diagnosis), Fever of unknown origin (FUO), pyrexia of unknown origin, FUO, Fever of unknown origin [FUO], Fever of Unknown Origin [Disease/Finding], fuo, unknown origin fever, f.u.o., fever of unknown origin fuo, fever unknown origin, fever origin unknown, Fever;unknown origin, fevers unknown origin, Pyrexia;unknown origin, f u o, fevers origin unknown, fever of origin unknown, [D]Pyrexia of unknown origin (situation), [D]Pyrexia of unknown origin NOS (situation), Pyrexia of unknown origin, F.U.O., Fever of unknown origin, PUO - Pyrexia of unknown origin, Pyrexia of unknown origin (finding), PUO; febris, febris; PUO, fever; unknown origin, hyperpyrexia; unknown origin, unknown origin; fever, unknown origin; hyperpyrexia, Fever of Unknown Origin |
Dutch | pyrexie van onbekende oorsprong, koorts van onbekende oorsprong, e.c.i.; febris, febris; e.c.i., hyperpyrexie; onbekende oorsprong, koorts; onbekende oorsprong, onbekende oorsprong; hyperpyrexie, onbekende oorsprong; koorts, Koorts door onbekende oorzaak |
French | Pyrexie d'origine inconnue, Fièvre d'origine inconnue |
German | Pyrexie unbekannter Ursache, Fieber unbekannter Ursache, Fieber unbekannter Genese |
Italian | Febbre di origine ignota, Piressia di origine sconosciuta, Febbre di origine sconosciuta |
Portuguese | Pirexia de origem desconhecida, Febre de origem desconhecida, Febre de Etiologia Desconhecida, Febre de Origem Desconhecida, Febre de Causa Desconhecida |
Spanish | Pirexia de origen desconocido, Fiebre de origen desconocido, [D]pirexia de origen desconocido (categoría dependiente del contexto), [D]pirexia de origen desconocido, SAI (categoría dependiente del contexto), [D]pirexia de origen desconocido, [D]pirexia de origen desconocido (situación), [D]pirexia de origen desconocido, SAI (situación), [D]pirexia de origen desconocido, SAI, Fiebre de Etiología Desconocida, fiebre de origen desconocido (hallazgo), fiebre de origen desconocido, F.O.D., Fiebre de Origen Desconocido |
Japanese | 不明熱, フメイネツ |
Swedish | Feber av okänt ursprung |
Czech | horečka neznámého původu, Horečka neznámého původu, Pyrexie neznámého původu, horečka nejasné etiologie |
Finnish | Epäselvä kuume |
Russian | LIKHORADKA NEIZVESTNOI ETIOLOGII, ЛИХОРАДКА НЕИЗВЕСТНОЙ ЭТИОЛОГИИ |
Korean | 기타 및 원인 미상의 열 |
Polish | Gorączka idiopatyczna, Gorączka o nieznanej etiologii |
Hungarian | Ismeretlen eredetű láz |
Norwegian | Feber med ukjent etiologi, Feber av ukjent årsak, Feber av ukjent opprinnelse, Febris causae ignotae |
Ontology: Prolonged fever (C0424768)
Concepts | Finding (T033) |
SnomedCT | 248435007 |
English | prolong fever, prolonged fever, fever prolong, fever prolonged, Prolonged fever, Prolonged fever (finding) |
Spanish | fiebre prolongada (hallazgo), fiebre prolongada |