AKT · Infections/Sepsis, fever & healthcare-associatedlow yield

Pyrexia of unknown origin

Prolonged fever (>3 weeks) without a diagnosis despite initial investigation — broad cause categories

Overview

Classically a fever >38.3°C on several occasions for more than 3 weeks that remains undiagnosed after appropriate initial investigation. The value of PUO is the structured differential: INFECTION (abscess, TB, endocarditis, HIV), MALIGNANCY (lymphoma, leukaemia, renal cell carcinoma), CONNECTIVE-TISSUE/autoimmune disease (adult Still's, vasculitis, GCA/PMR), and MISCELLANEOUS (drugs, thromboembolism, factitious). The approach is methodical, history-driven, and avoids blind antibiotics.

Recognise

Persistent/recurrent fever >3 weeks, undiagnosed after initial work-up; associated weight loss, night sweats, rashes, arthralgia, lymphadenopathy depending on cause
Categories: Infection (occult abscess, TB, infective endocarditis, HIV, brucellosis), Malignancy (lymphoma, leukaemia, RCC), Connective-tissue (adult-onset Still's, GCA/PMR, vasculitis, SLE), Miscellaneous (drug fever, VTE, factitious)
Travel, occupational, animal, sexual and drug histories reshape the differential

Red flags

Don't give blind/empirical antibiotics or steroids before a diagnosis (unless septic) — they obscure the picture
Localising clues guide targeted investigation; consider HIV in everyone

Differentials & how to tell them apart

Occult infectionabscess, TB, infective endocarditis (echo + cultures), HIV — the commonest PUO category

Malignancylymphoma (LDH, lymphadenopathy), leukaemia, renal cell carcinoma

Connective-tissue diseaseadult-onset Still's (salmon rash, raised ferritin), GCA/PMR (over-50, raised ESR), vasculitis/SLE

Drug fever / factitiousculprit drug; factitious — discrepant findings, healthcare worker

Investigations

Thorough repeated history + examination; FBC/film, CRP/ESR, U&Es/LFTs, blood cultures (×3, off antibiotics), urinalysis/culture, HIV test, autoimmune screen (ANA/ANCA), TFTs, LDH; imaging (CXR, CT chest/abdomen/pelvis, echocardiogram for endocarditis); ± PET-CT, biopsy (node/marrow/temporal artery) directed by clues.

Management

Structured clue-directed work-up → treat the identified cause (avoid blind antibiotics)

1Confirm true PUO (fever >3 weeks, undiagnosed after initial work-up) and frame the four categories (infection/malignancy/connective-tissue/miscellaneous). Take detailed travel/occupational/animal/sexual/drug histories and investigate systematically, including an HIV test.Gate: Do NOT give blind antibiotics or steroids before a diagnosis (unless the patient is septic) — they obscure the picture; let localising clues direct targeted tests/biopsy.
2Escalate to CT/PET and directed biopsy (node/marrow/temporal artery) guided by clues; treat the specific cause once found.

Systematic, clue-directed investigation (no blind antibiotics) — the management IS the structured work-up; avoid empirical antibiotics/steroids that mask the diagnosis (unless the patient is septic)

Treat the cause once identified — antibiotics for the specific infection, oncology for malignancy, immunosuppression for connective-tissue disease

Stop non-essential drugs (drug fever) — a therapeutic trial of stopping a suspected culprit

Empirical therapy only in specific scenarios — e.g. culture-negative endocarditis or suspected TB after appropriate work-up — specialist-led

Key points

Fever >3 weeks, undiagnosed after initial work-up = PUO → think in 4 categories: INFECTION (abscess/TB/endocarditis/HIV), MALIGNANCY (lymphoma/leukaemia/RCC), CONNECTIVE-TISSUE (adult Still's/GCA/vasculitis), MISCELLANEOUS (drug fever/VTE/factitious). Methodical clue-directed work-up; HIV test everyone; don't give blind antibiotics.

Monitor & prognosis

Evolving clues, investigation yield, response once the cause is treated.

Depends on the cause; many resolve or are diagnosed with persistence; some remain undiagnosed and self-limit.

Source: Infectious-diseases references; cross-ref haematology, MSK (GCA/Still's), sexual_health (HIV)