Infectious Disease · Topic 3 of 10
Fever of Unknown Origin & New Fever in the Hospital
Infectious disease · fever evaluation
Fever of Unknown Origin & New Fever in the Hospital
Classic FUO is ≥ 38.3 °C for over 3 weeks with no cause after a basic work-up; infection is still the most common cause.
Key numbers
≥ 38.3 °C for over 3 weeks≥ 38.3 °C, > 3 wk
Two blood culture sets before antibiotics≥ 2 sets, ~60 mL
01 · What it is≥ 38.3 °C for over 3 weeks
Classic FUO = temperature ≥ 38.3 °C (101 °F) for more than 3 weeks with no cause found after 3 days of hospital evaluation or at least 3 outpatient visits.
02 · CauseInfection is the most common cause
FUO causes in adults: infection 25–50% (most common), systemic rheumatic disease 10–20%, neoplasm 2–25%, and miscellaneous 15–25%; no cause is found in about 10%.
03 · DoTwo blood culture sets before antibiotics
For new hospital or ICU fever, draw at least 2 blood culture sets (ideally 60 mL total) from different sites; with a central line and no obvious source, draw line and peripheral cultures together.
01
What it is
Core ideaHealth care–associated FUO: undiagnosed after 3 days must knowHealth care–associated (nosocomial) FUO = fever in a hospitalized patient with no infection present or incubating on admission whose cause remains uncertain after 3 days of appropriate evaluation.
02
Causes & risk factors
Why it happensOlder adults: think giant cell arteritisIn older adults with FUO, the most common causes are giant cell arteritis, lymphoma, abscess and tuberculosis; unexplained high ESR prompts evaluation for giant cell arteritis, including temporal artery biopsy.
Drug fever is a diagnosis of exclusionDrug fever, with or without rash, is a diagnosis of exclusion confirmed by stopping the drug; common culprits are beta-lactams, sulfonamides, phenytoin, carbamazepine, procainamide, quinidine and amphotericin B.
Hospital fever: lines, urine, lungs, wounds, clots, drugsCommon sources of new fever in a hospitalized patient: catheter-associated bloodstream infection, catheter-associated UTI, pneumonia (especially ventilated), surgical site infection, C. difficile diarrhea, DVT/PE, drug fever and transfusion reaction.
03
Diagnosis & monitoring
Work-upProcalcitonin if bacterial probability low–intermediateWhen the probability of bacterial infection is low to intermediate, add procalcitonin (or CRP) to bedside evaluation; when probability is high, do not use procalcitonin or CRP to rule out bacterial infection.
04
Do right now
In this orderFirst moves
1
→Two blood culture sets before antibiotics≥ 2 sets, ~60 mL
2
→Chest radiograph for new ICU fever
3
Recent surgery: CT if initial work-up is negative
Why each step
Two blood culture sets before antibioticsFor new hospital or ICU fever, draw at least 2 blood culture sets (ideally 60 mL total) from different sites; with a central line and no obvious source, draw line and peripheral cultures together.
Chest radiograph for new ICU feverObtain a chest radiograph for every patient who develops fever during an ICU stay; add bedside thoracic ultrasound when the film is abnormal and expertise is available.
Recent surgery: CT if initial work-up is negativeAfter recent thoracic, abdominal or pelvic surgery, get CT (with the surgical team) if the initial work-up finds no cause; order formal abdominal ultrasound for abdominal signs or recent abdominal surgery, not routinely.
05
Management
OrdersFever with pyuria: replace catheter, then cultureIn a febrile ICU patient with an indwelling urinary catheter, pyuria and suspected UTI, replace the catheter and send urine culture from the new catheter.
Avoid routine antipyretics just to lower temperatureIn critically ill patients, avoid routine antipyretics given only to lower the temperature; give them for comfort when the patient values it, in preference to physical cooling.
Baseline FUO labs and serial blood culturesBaseline FUO tests: CBC with differential, ESR, CRP, procalcitonin, LDH, ferritin, liver tests, urinalysis with microscopy, serial blood cultures before antibiotics, HIV testing, and tuberculin skin test or IGRA.
CT chest, abdomen and pelvis; consider PETImage symptomatic areas first, and consider CT of the chest, abdomen and pelvis for occult abscess or adenopathy even without localizing signs; PET helps localize inflammation, and abnormal tissue is biopsied and cultured.
06
Fever or hyperthermia?
Commonly confused| Mechanism | Hypothalamic set point reset upward |
|---|---|
| Extreme temperature (> 41 °C) | Uncommon |
| Typical causes | Infection, rheumatic disease, cancer, drug hypersensitivity |
07
More detail
ReferenceShow 8 reference facts
Use central temperature (pulmonary artery, bladder or esophageal thermistor) when such a device is in place; otherwise prefer oral or rectal readings over axillary, tympanic or temporal artery thermometers.
Treatment of FUO is directed at the underlying cause once found; antipyretics are used judiciously, weighing how long the fever has lasted.
Immunodeficiency-related FUO: neutropenia or transplant with no cause after 3 days including 48 hours of negative cultures; HIV-related FUO is fever > 4 weeks as an outpatient or > 3 days as an inpatient.
Repeat the history yourself rather than copying earlier notes (travel, occupation, animals, diet, drugs, family history), and re-examine repeatedly for a new murmur, adenopathy, rash or temporal artery tenderness.
FUO red flags are immunocompromise, a heart murmur, implanted devices (IV lines, pacemakers, joint prostheses) and recent travel to an endemic area.
Neoplastic FUO is usually lymphoma, leukemia, renal cell or hepatocellular carcinoma, or metastatic cancer; miscellaneous causes include drug reactions, DVT, recurrent PE, thyroiditis, sarcoidosis, IBD and factitious fever.
Fever is a resetting of the hypothalamic set point, usually in response to infection; a raised temperature without a set-point change is hyperthermia.
If rapid molecular tests are run on blood for new ICU fever, use them only together with conventional blood cultures.
In FUO, take the history again yourself and re-examine often — the clue is usually missed, not missing.
Sources · Merck Manual Professional — Fever of Unknown Origin (FUO) (cites Haidar G, Singh N. N Engl J Med 2022;386:463–477) · O'Grady NP et al. SCCM and IDSA Guidelines for Evaluating New Fever in Adult Patients in the ICU. Crit Care Med 2023;51:1570–1586 (abstract via Europe PMC; recommendation text excerpted at tomwademd.net) · Merck Manual Professional — Fever in Adults · Excerpts of the 2023 SCCM/IDSA new-fever-in-the-ICU recommendations (Tom Wade MD) · Starter sheet built from the verified AGACNP fact map (facts reviewed 2026-10-15).