Stethopedia | Approach

Approach to

Fever of Unknown Origin

Confirm prolonged fever, do the minimum workup, act at once on instability, immunocompromise, GCA or HLH, then sort by category (Fusco 2019 shares). PET/CT if CT is non-diagnostic; avoid empiric antibiotics and steroids.

  1. Fever ≥38.3 °C on several occasions for ≥3 wk, still undiagnosed
  2. Confirm fever; repeat full history (travel, animals, drugs) and exam; stop non-essential drugs1,2
  3. CBC, smear, CMP, LDH, ESR, CRP, ferritin, 3 BCx, UA, HIV, IGRA, CXR; CT C/A/P, then PET/CT2,6,12
  4. Unstable, high-risk host, GCA or HLH?

High risk: culture, treat, admit, consult2,12

  • Hypotension or sepsis
  • Neutropenia: ANC <0.5 ×10⁹/L
  • Transplant, biologics, AIDS
  • Vision loss, jaw claudication: GCA
  • Ferritin >3000 µg/L, cytopenias, spleen: HLH

→ Cultures first; GCA: prednisone 40–60 mg now; rheum ≤24 h8,12

If stable: which category?

CausesCluesWorkupManagement

Infection

  • Endocarditis (incl. culture-negative)
  • TB (extrapulmonary), occult abscess
  • Malaria; EBV, CMV, HIV; brucella, Q fever
  • Murmur, emboli; valve, device, IDU7
  • Travel, animals, raw milk, TB birthplace
  • Night sweats; dental or surgical history
  • 3 culture sets before antibiotics; echo7
  • IGRA; malaria smears; serology1,12
  • Tissue biopsy: histology, AFB culture12
  • Treat organism; drain abscess
  • No empiric antibiotics if stable1,12

Inflammatory

  • Giant cell arteritis, PMR
  • Adult-onset Still disease
  • SLE, vasculitis, sarcoid, IBD
  • Age >50: headache, jaw claudication
  • Daily spikes, salmon rash, arthritis1
  • High ESR/CRP; very high ferritin (Still)
  • ANA, RF, ANCA, CK, ferritin, SPEP12
  • Temporal + axillary ultrasound first9
  • Temporal biopsy if ≥55 y, no lead4
  • GCA: prednisone 40–60 mg now; rheum ≤24 h8
  • Otherwise no empiric steroids1

Neoplasm

  • Lymphoma
  • Leukemia, myeloproliferative, myeloma
  • Renal cell, liver, colon cancer
  • Drenching sweats, weight loss, nodes
  • High LDH, cytopenias, splenomegaly
  • SPEP, free light chains; smear review12
  • PET/CT unhelpful if ESR, CRP normal5
  • Excisional node, liver or marrow biopsy
  • Tissue before any steroids1
  • Hematology or oncology referral

Other

  • Drug fever; VTE, hematoma
  • HLH
  • Thyroiditis, periodic fever, factitious
  • β-lactam, ASM; rash, eosinophilia uncommon12
  • Ferritin >3000 µg/L, cytopenias, ↑TG12
  • Episodic fever, well between4
  • Stop drug: fever settles in ≤1 wk12
  • HScore; sIL-2R, marrow biopsy10,11
  • Leg Doppler; TSH; fever diary
  • HLH: dexamethasone ± etoposide11
  • No diagnosis in 23–51% of FUO3,4
  • Then observe: most resolve12

Can't-miss cause Superscripts link to the references below.

References

  1. Haidar G, Singh N. Fever of unknown origin. N Engl J Med. 2022;386:463–477. PubMed 35108471
  2. Wright WF, Stelmash L, Betrains A, et al. Recommendations for updating fever and inflammation of unknown origin from a modified Delphi consensus panel. Open Forum Infect Dis. 2024;11:ofae298. PubMed 38966848
  3. Fusco FM, Pisapia R, Nardiello S, et al. Fever of unknown origin (FUO): which are the factors influencing the final diagnosis? A 2005–2015 systematic review. BMC Infect Dis. 2019;19:653. PubMed 31331269
  4. Bleeker-Rovers CP, Vos FJ, de Kleijn EMHA, et al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore). 2007;86:26–38. PubMed 17220753
  5. Bleeker-Rovers CP, Vos FJ, Mudde AH, et al. A prospective multi-centre study of the value of FDG-PET as part of a structured diagnostic protocol in patients with fever of unknown origin. Eur J Nucl Med Mol Imaging. 2007;34:694–703. PubMed 17171357
  6. Takeuchi M, Dahabreh IJ, Nihashi T, et al. Nuclear imaging for classic fever of unknown origin: meta-analysis. J Nucl Med. 2016;57:1913–1919. PubMed 27339873
  7. Fowler VG, Durack DT, Selton-Suty C, et al. The 2023 Duke-International Society for Cardiovascular Infectious Diseases criteria for infective endocarditis: updating the modified Duke criteria. Clin Infect Dis. 2023;77:518–526. PubMed 37138445
  8. Mukhtyar CB, Nikiphorou E, Bartoletti A, et al. 2025 EULAR recommendations for the management of polymyalgia rheumatica and primary large vessel vasculitis. Ann Rheum Dis. 2026. doi:10.1016/j.ard.2026.06.009. PubMed 42481270
  9. Dejaco C, Ramiro S, Bond M, et al. EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice: 2023 update. Ann Rheum Dis. 2024;83:741–751. PubMed 37550004
  10. Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66:2613–2620. PubMed 24782338
  11. La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133:2465–2477. PubMed 30992265
  12. Enns J, Kendall E, eds. Fever of Unknown Origin; Hemophagocytic Lymphohistiocytosis. In: Department of Medicine Housestaff Manual, 30th ed. 2024:129, 134.

For education only; not a substitute for clinical judgment or local protocols. Where sources differ, the flowchart follows the current guideline.

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