Synopsis
Investigate prolonged unexplained fever through a disciplined exposure-led and syndrome-led process that identifies time-critical infection without indiscriminate testing or premature empirical treatment.
- Confirm that fever is objectively present, sustained or recurrent, and not explained by measurement error, normal diurnal variation or transient self-limited infection.
- Repeat the history because diagnostic clues emerge over time: travel, animals, occupation, dental work, implants, medicines, immune suppression, sexual exposure and family origin all matter.
- Examine repeatedly for lymph nodes, rash, murmurs, temporal tenderness, synovitis, hepatosplenomegaly, spinal tenderness, focal neurological signs and device or surgical-site changes.
- Build four parallel categories—infection, malignancy, inflammatory disease and miscellaneous causes—then let positive findings determine tests rather than ordering every available panel.
- Blood cultures, urine testing, HIV testing with consent, chest imaging and a core haematological, renal, hepatic and inflammatory screen commonly form the first tier.
- Avoid empirical antibiotics in a stable undifferentiated patient because partial treatment reduces microbiological yield; treat immediately when instability, neutropenia or a defined dangerous syndrome changes the balance.
- A negative scan or marker does not close the case. Review the fever curve, medicines, repeated examination, new localising symptoms and whether the original definition remains valid.
Key red flags
Persistent bacteraemia, a new murmur, embolic features, prosthetic valve, cardiac device or injection exposure raises infective endocarditis and requires multiple cultures and echocardiographic planning.
Headache with temporal tenderness, synovitis, rash, myalgia, serositis, renal sediment or recurrent mucosal inflammation supports vasculitic, connective-tissue or autoinflammatory disease.
Investigation priorities
Confirm the phenotype and capture new localising clues over time.
Management branches
Documented recurrent fever with no high-risk physiology and no established diagnosis after initial assessment.
- Reconstruct the timeline and exposures, repeat a complete examination, verify fever and stop non-essential medicines safely when drug fever is plausible.
- Obtain a focused first-tier screen and cultures before antimicrobials, then select serology, imaging and specialty referral from genuine potential diagnostic clues.
- Review all results together at a defined interval, pursue tissue from the safest highest-yield lesion and resist repeating low-yield tests without a changed hypothesis.
Fever continues despite negative first-line cultures, imaging and targeted serology in a clinically stable patient.
- Audit temperature documentation, medicine exposure, travel and prior antimicrobial history, and repeat examination for lymph nodes, vascular, ocular, cardiac, spinal and skin signs.
- Review pathology and radiology with relevant specialists, consider echocardiography or PET-CT only when it can locate a diagnostic target, and plan biopsy specimens before the procedure.
- Avoid diagnostic corticosteroids unless an organ-threatening inflammatory syndrome justifies them; document surveillance and safety-netting if no cause is found.